BIOPHARMACEUTICS CLASSIFICATION

SYSTEM

Contents bull Introduction bull Overview of the Classification

systembull Applicationsbull Conclusion bull References

Introduction

Biopharmaceutics Classification System (BCS)

Scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability

What is the need for a classification based on

biopharmaceutics of the drugbull Ans Its importance in determining bioavailability

spadesRoute of choice for the formulators Continues to dominate the area of drug delivery

technologies

LIMITATIONS Absorption and Bioavailability in the milieu of

gastrointestinal tract Limitations more prominent

with the advent of protein and peptide drugs compounds emerging as a result of combinatorial chemistry and

the technique of high throughput screening

ORAL ROUTE

drug solubilitydrug product quality attributes

API structure salt form and

excipients

Bioavailability of drug is determined by

extent of drug solubility and

permeability

Guidance provided by the US Food and Drug Administration for predicting the intestinal drug

absorption

The fundamental basis established by

Dr Gordon Amidon Distinguished Science Award (Aug rsquo06 FIP)

First introduced into regulatory decision-making process in the guidance document on Immediate Release Solid Oral Dosage

Forms Scale Up And Post Approval Changes

Biopharmaceutics Classification System

Drug development tool that allows estimation of the contributions of 3 major factors that affect oral drug absorption from immediate release solid oral dosage forms

DissolutionSolubility

Intestinal permeability

The Biopharmaceutics Classification System (BCS)(as defined by the FDA after Amidon)

SIMILAR IN VIVO DISSOLUTION

SIMILAR IN VIVO ABSORPTION

SIMILAR SYSTEMIC AVAILABILITY

Dissolution of drug in vivo

Drug Concentration in the Membrane Domain

Intestinal Absorption

determines

proportional

Basis of BCS

(37plusmn100C in aqueous medium with pH range of 1-75)

A sufficient number of pH conditions ionization characteristics of the test drug substance

A minimum of three replicate determinations of solubility in each pH condition

Standard buffer solutions described in pharmacopoeias Methods other than shake flask method (with

Justification) e g acid or base titration methods

SOLUBILITY DETERMINATION

clubsNot just based on lipophilicity (encompass in vivo effects of efflux and uptake transporters)

A Human studies Mass balance studies Absolute bioavailability studies Intestinal perfusion methods

BIn vivo or in situ intestinal perfusion in a suitable animal model

CIn vitro permeability methods using excised intestinal tissues

D In vitro permeation studies across a monolayer of cultured epithelial cellseg Caco-2 cells or TC-7 cells

Determination of permeability

DISSOLUTION DETERMINATION

USP apparatus I (basket) at 100 rpm or USP apparatus II (paddle) at 50 rpm

Dissolution media (900 ml) 01 N HCl or simulated gastric fluid pH 45 buffer and pH 68 buffer or simulated intestinal fluid

Compare dissolution profiles of test and reference products using a similarity factor (f2)

0

CLASS BOUNDARIES

HIGHLY SOLUBLE the highest dose strength is soluble in lt 250 ml water over a pH range of 1 to 75

The volume estimate-a glassful (8 ounce)

HIGHLY PERMEABLE when the extent of absorption in humans is determined to be gt 90 of an administered dose

RAPIDLY DISSOLVING when gt 85 of the labeled amount of drug substance dissolves within 30 minutes using USP apparatus I or II in a volume of lt 900 ml buffer solutions

BCS Class Boundaries Objectives

Dissolution(Product)

Solubility (Drug)

Permeability

(Drug)

Rapid dissolution - ensure that in vivo dissolution is not likely to be theldquorate determiningrdquo step

High solubility- ensure that solubilityis not likely to limit dissolution and therefore absorption

High permeability - ensure that drugis completely absorbed during the limitedtransit time through the small intestine

BCS -Implications for drug developmentЖApplication in early drug development and then in

the management of product change through its life cycle

ЖAids fundamental understanding of the biopharmaceutical and physical properties of the drug

ЖAids discriminatory dissolution method development

ЖCan help guide the development of in-vitroin-vivo correlations

ЖCan be used to obtain a biowaiver

ЖDevelopment of poorly soluble drugs

This classification is associated with drug dissolution and absorption model which identifies the key parameters controlling drug absorption as a set of dimensionless numbers viz

BCS defines 3 numbers (no units)

An ~ absorption number Do ~ dose number Dn ~ dissolution number

ABS

GI

GI

eff

TT

TR

PAn

Effective permeability

Radius of GI

Residence time in GI

Time required forcomplete absorption

Absorption NumberA function of GI Permeability to Drug Substance

S

Water

CV

DDo

Highest Dose Unit

250 mL

Solubility

Dose NumberA function of solubility of drug substance

Solubility mgmL

DISS

GI

GI

S

TT

TC

rD

Dn2

3Diffusivity5x10-6 cm2s

Density12 mgcm3

Particle Radiusm

Residence time in GI 180 min

Time required forcomplete dissolution

Dissolution NumberA function of drug release from formulation

IVIVC expectations for immediate release products based on BCS

Class Solubility Permeability Absorption rate control

IVIVC expectations for Immediate release product

I High High Gastric emptying

IVIVC expected if dissolution rate is slower than gastric emptying rate otherwise limited or no correlations

II Low High Dissolution IVIVC expected if in vitro dissolution rate is similar to in vivo dissolution rate unless dose is very high

III High Low Permeability Absorption (permeability) is rate determining and limited or no IVIVC with dissolution

IV Low Low Case by case

Limited or no IVIVC is expected

High Solubility Low Solubility H

igh

Pe

rmea

bil

ity

Class 1 Abacavir Acetaminophen Acyclovirb AmilorideSI

Amitryptyline SI Antipyrine Atropine Buspironec Caffeine Captopril ChloroquineSI

Chlorpheniramine Cyclophosphamide Desipramine Diazepam Diltiazem SI Diphenhydramine Disopyramide Doxepin Doxycycline Enalapril Ephedrine Ergonovine Ethambutol Ethinyl Estradiol FluoxetineI

Glucose

ImipramineI Ketorolac Ketoprofen Labetolol LevodopaS Levofloxacin S LidocaineI Lomefloxacin Meperidine Metoprolol Metronidazole MidazolamSI Minocycline Misoprostol Nifedipine S Phenobarbital Phenylalanine Prednisolone PrimaquineS Promazine Propranolol I QuinidineSI Rosiglitazone Salicylic acid Theophylline Valproic acid Verapamil I Zidovudine

Class 2 Amiodarone I AtorvastatinS I AzithromycinS I

Carbamazepine SI Carvedilol Chlorpromazine I CisaprideS

Ciprofloxacin S Cyclosporine S I Danazol Dapsone Diclofenac Diflunisal Digoxin S Erythromycin SI Flurbiprofen Glipizide GlyburideSI Griseofulvin Ibuprofen Indinavir S

Indomethacin

Itraconazole SI Ketoconazole I LansoprazoleI Lovastatin SI Mebendazole Naproxen Nelfinavir SI Ofloxacin Oxaprozin Phenazopyridine PhenytoinS Piroxicam Raloxifene S Ritonavir SI Saquinavir SI Sirolimus S Spironolactone I Tacrolimus SI TalinololS

Tamoxifen I Terfenadine I Warfarin

High Solubility Low Solubility Lo

w P

erm

eabi

lity

Class 3 Acyclovir Amiloride SI Amoxicillin SI Atenolol Atropine Bisphosphonates Bidisomide Captopril Cefazolin Cetirizine Cimetidine S Ciprofloxacin S Cloxacillin Dicloxacillin S Erythromycin SI

Famotidine

Fexofenadine S Folinic acid Furosemide Ganciclovir Hydrochlorothiazide Lisinopril Metformin Methotrexate Nadolol Pravastatin S Penicillins Ranitidine S Tetracycline Trimethoprim S Valsartan Zalcitabine

Class 4 Amphotericin B Chlorthalidone Chlorothiazide Colistin Ciprofloxacin S Furosemide Hydrochlorothiazide Mebendazole Methotrexate Neomycin

Applications of BCS in oral drug delivery technology

Achieve a target release profile associated with a particular pharmacokinetic andor pharmacodynamic profile

Formulation approaches include both control of release rate and certain physicochemical properties of drugs like pH-solubility profile of drug

Class I - High Permeability High Solubility

Micronisation

Addition of surfactants

Formulation as emulsions and microemulsions systems

Use of complexing agents like cyclodextrins

Class II - High Permeability

Low Solubility

Require the technologies that address to fundamental limitations of absolute or regional permeability

Peptides and proteins constitute the part of class III and the technologies handling such materials are on rise now days

Class III - Low Permeability High Solubility

Class IV - Low Permeability Low Solubility

Major challenge for development of drug delivery system and the route of choice for administering such drugs is parenteral (solubility enhancers)

Fortunately extreme examples are the exception rather than the rule and are rarely developed and reach the market

Biowaiver A biowaiver is an exemption from

conducting human bioequivalence studies when the active ingredient(s) meet certain solubility and permeability criteria in vitro and when the dissolution profile of the dosage form meets the requirements for an immediate release dosage form

Waiver of In Vivo Bioequivalence Study based on

Pharmaceutical Dosage Form (Solutions)

Biopharmaceutics Classification System

Dose (Highest Strength should be tested)

BCS BIOWAIVER

Biowaiver for

Rapid and similar dissolution High solubility ampHigh permeability Wide therapeutic window Excipients used in dosage form used

previously in approved IR solid dosage forms

REQUEST FOR BIOWAIVERS

Data Supporting -

Rapid and Similar Dissolution

High Permeability

High Solubility

Limitations of BCS as a Predictor of Drug

DispositionΩ Permeability (90 absorption) is difficult to

determine and difficult to convince the regulatory agency

Ω There is little predictability for BCS classification drugs beyond Class 1 primarily due to the difficulty of determining and proving 90 absorption many drugs are misclassified (eg HIV protease inhibitors

as Class 4 compounds))

Conclusion BCS aims to provide a regulatory tool for

replacing certain BE studies by accurate in-vitro dissolution tests

This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in

drug molecules with a sufficiently high permeability solubility and dissolution

rate and that will automatically increase the importance of the BCS as

a regulatory tool over time

References Draft guidance for industry waiver of in vivo

bioavailability and bioequivalence studies for immediate release solid oral dosage forms containing certain active moieties active ingredients based on a biopharmaceutic classification system february 1999 CDERFDA

Amidon GL Lennernas H Shah VP Crison JRA A theoretical basis for a biopharmaceutic drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharm Res 12 413-420 (1995)

Guidance for industry immediate release solid oral dosage forms scale up and post approval changes november 1995 CDERFDA

Medicamento generico from website httpwwwAnvisaGo

Devane J Oral drug delivery technology addressing the solubility permeability paradigm pharm Technol 68-74 november 1998

Amidon G LLennernaumls H Shah V P And crisonj R A theoretical basis for a biopharmaceutics drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharmaceutical research 12 413-420 (1995)

Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA CDER 1997 1048603httpwwwfdagovcderguidance1713bp1pdf

Guidance for Industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System FDA CDER August 2000 httpwwwfdagovcderguidance3618fnlhtm

Thank you

• BIOPHARMACEUTICS CLASSIFICATION SYSTEM
• Contents
• Introduction
• Slide 4
• Slide 5
• Biopharmaceutics Classification System
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• DISSOLUTION DETERMINATION
• CLASS BOUNDARIES
• BCS Class Boundaries Objectives
• Slide 15
• BCS -Implications for drug development
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Applications of BCS in oral drug delivery technology
• Class II - High Permeability Low Solubility
• Slide 27
• Slide 28
• Biowaiver
• Waiver of In Vivo Bioequivalence Study based on
• BCS BIOWAIVER
• REQUEST FOR BIOWAIVERS
• Limitations of BCS as a Predictor of Drug Disposition
• Conclusion
• References
• Slide 36
• Slide 37

Contents bull Introduction bull Overview of the Classification

systembull Applicationsbull Conclusion bull References

Introduction

Biopharmaceutics Classification System (BCS)

Scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability

What is the need for a classification based on

biopharmaceutics of the drugbull Ans Its importance in determining bioavailability

spadesRoute of choice for the formulators Continues to dominate the area of drug delivery

technologies

LIMITATIONS Absorption and Bioavailability in the milieu of

gastrointestinal tract Limitations more prominent

with the advent of protein and peptide drugs compounds emerging as a result of combinatorial chemistry and

the technique of high throughput screening

ORAL ROUTE

drug solubilitydrug product quality attributes

API structure salt form and

excipients

Bioavailability of drug is determined by

extent of drug solubility and

permeability

Guidance provided by the US Food and Drug Administration for predicting the intestinal drug

absorption

The fundamental basis established by

Dr Gordon Amidon Distinguished Science Award (Aug rsquo06 FIP)

First introduced into regulatory decision-making process in the guidance document on Immediate Release Solid Oral Dosage

Forms Scale Up And Post Approval Changes

Biopharmaceutics Classification System

Drug development tool that allows estimation of the contributions of 3 major factors that affect oral drug absorption from immediate release solid oral dosage forms

DissolutionSolubility

Intestinal permeability

The Biopharmaceutics Classification System (BCS)(as defined by the FDA after Amidon)

SIMILAR IN VIVO DISSOLUTION

SIMILAR IN VIVO ABSORPTION

SIMILAR SYSTEMIC AVAILABILITY

Dissolution of drug in vivo

Drug Concentration in the Membrane Domain

Intestinal Absorption

determines

proportional

Basis of BCS

(37plusmn100C in aqueous medium with pH range of 1-75)

A sufficient number of pH conditions ionization characteristics of the test drug substance

A minimum of three replicate determinations of solubility in each pH condition

Standard buffer solutions described in pharmacopoeias Methods other than shake flask method (with

Justification) e g acid or base titration methods

SOLUBILITY DETERMINATION

clubsNot just based on lipophilicity (encompass in vivo effects of efflux and uptake transporters)

A Human studies Mass balance studies Absolute bioavailability studies Intestinal perfusion methods

BIn vivo or in situ intestinal perfusion in a suitable animal model

CIn vitro permeability methods using excised intestinal tissues

D In vitro permeation studies across a monolayer of cultured epithelial cellseg Caco-2 cells or TC-7 cells

Determination of permeability

DISSOLUTION DETERMINATION

USP apparatus I (basket) at 100 rpm or USP apparatus II (paddle) at 50 rpm

Dissolution media (900 ml) 01 N HCl or simulated gastric fluid pH 45 buffer and pH 68 buffer or simulated intestinal fluid

Compare dissolution profiles of test and reference products using a similarity factor (f2)

0

CLASS BOUNDARIES

HIGHLY SOLUBLE the highest dose strength is soluble in lt 250 ml water over a pH range of 1 to 75

The volume estimate-a glassful (8 ounce)

HIGHLY PERMEABLE when the extent of absorption in humans is determined to be gt 90 of an administered dose

RAPIDLY DISSOLVING when gt 85 of the labeled amount of drug substance dissolves within 30 minutes using USP apparatus I or II in a volume of lt 900 ml buffer solutions

BCS Class Boundaries Objectives

Dissolution(Product)

Solubility (Drug)

Permeability

(Drug)

Rapid dissolution - ensure that in vivo dissolution is not likely to be theldquorate determiningrdquo step

High solubility- ensure that solubilityis not likely to limit dissolution and therefore absorption

High permeability - ensure that drugis completely absorbed during the limitedtransit time through the small intestine

BCS -Implications for drug developmentЖApplication in early drug development and then in

the management of product change through its life cycle

ЖAids fundamental understanding of the biopharmaceutical and physical properties of the drug

ЖAids discriminatory dissolution method development

ЖCan help guide the development of in-vitroin-vivo correlations

ЖCan be used to obtain a biowaiver

ЖDevelopment of poorly soluble drugs

This classification is associated with drug dissolution and absorption model which identifies the key parameters controlling drug absorption as a set of dimensionless numbers viz

BCS defines 3 numbers (no units)

An ~ absorption number Do ~ dose number Dn ~ dissolution number

ABS

GI

GI

eff

TT

TR

PAn

Effective permeability

Radius of GI

Residence time in GI

Time required forcomplete absorption

Absorption NumberA function of GI Permeability to Drug Substance

S

Water

CV

DDo

Highest Dose Unit

250 mL

Solubility

Dose NumberA function of solubility of drug substance

Solubility mgmL

DISS

GI

GI

S

TT

TC

rD

Dn2

3Diffusivity5x10-6 cm2s

Density12 mgcm3

Particle Radiusm

Residence time in GI 180 min

Time required forcomplete dissolution

Dissolution NumberA function of drug release from formulation

IVIVC expectations for immediate release products based on BCS

Class Solubility Permeability Absorption rate control

IVIVC expectations for Immediate release product

I High High Gastric emptying

IVIVC expected if dissolution rate is slower than gastric emptying rate otherwise limited or no correlations

II Low High Dissolution IVIVC expected if in vitro dissolution rate is similar to in vivo dissolution rate unless dose is very high

III High Low Permeability Absorption (permeability) is rate determining and limited or no IVIVC with dissolution

IV Low Low Case by case

Limited or no IVIVC is expected

High Solubility Low Solubility H

igh

Pe

rmea

bil

ity

Class 1 Abacavir Acetaminophen Acyclovirb AmilorideSI

Amitryptyline SI Antipyrine Atropine Buspironec Caffeine Captopril ChloroquineSI

Chlorpheniramine Cyclophosphamide Desipramine Diazepam Diltiazem SI Diphenhydramine Disopyramide Doxepin Doxycycline Enalapril Ephedrine Ergonovine Ethambutol Ethinyl Estradiol FluoxetineI

Glucose

ImipramineI Ketorolac Ketoprofen Labetolol LevodopaS Levofloxacin S LidocaineI Lomefloxacin Meperidine Metoprolol Metronidazole MidazolamSI Minocycline Misoprostol Nifedipine S Phenobarbital Phenylalanine Prednisolone PrimaquineS Promazine Propranolol I QuinidineSI Rosiglitazone Salicylic acid Theophylline Valproic acid Verapamil I Zidovudine

Class 2 Amiodarone I AtorvastatinS I AzithromycinS I

Carbamazepine SI Carvedilol Chlorpromazine I CisaprideS

Ciprofloxacin S Cyclosporine S I Danazol Dapsone Diclofenac Diflunisal Digoxin S Erythromycin SI Flurbiprofen Glipizide GlyburideSI Griseofulvin Ibuprofen Indinavir S

Indomethacin

Itraconazole SI Ketoconazole I LansoprazoleI Lovastatin SI Mebendazole Naproxen Nelfinavir SI Ofloxacin Oxaprozin Phenazopyridine PhenytoinS Piroxicam Raloxifene S Ritonavir SI Saquinavir SI Sirolimus S Spironolactone I Tacrolimus SI TalinololS

Tamoxifen I Terfenadine I Warfarin

High Solubility Low Solubility Lo

w P

erm

eabi

lity

Class 3 Acyclovir Amiloride SI Amoxicillin SI Atenolol Atropine Bisphosphonates Bidisomide Captopril Cefazolin Cetirizine Cimetidine S Ciprofloxacin S Cloxacillin Dicloxacillin S Erythromycin SI

Famotidine

Fexofenadine S Folinic acid Furosemide Ganciclovir Hydrochlorothiazide Lisinopril Metformin Methotrexate Nadolol Pravastatin S Penicillins Ranitidine S Tetracycline Trimethoprim S Valsartan Zalcitabine

Class 4 Amphotericin B Chlorthalidone Chlorothiazide Colistin Ciprofloxacin S Furosemide Hydrochlorothiazide Mebendazole Methotrexate Neomycin

Applications of BCS in oral drug delivery technology

Achieve a target release profile associated with a particular pharmacokinetic andor pharmacodynamic profile

Formulation approaches include both control of release rate and certain physicochemical properties of drugs like pH-solubility profile of drug

Class I - High Permeability High Solubility

Micronisation

Addition of surfactants

Formulation as emulsions and microemulsions systems

Use of complexing agents like cyclodextrins

Class II - High Permeability

Low Solubility

Require the technologies that address to fundamental limitations of absolute or regional permeability

Peptides and proteins constitute the part of class III and the technologies handling such materials are on rise now days

Class III - Low Permeability High Solubility

Class IV - Low Permeability Low Solubility

Major challenge for development of drug delivery system and the route of choice for administering such drugs is parenteral (solubility enhancers)

Fortunately extreme examples are the exception rather than the rule and are rarely developed and reach the market

Biowaiver A biowaiver is an exemption from

conducting human bioequivalence studies when the active ingredient(s) meet certain solubility and permeability criteria in vitro and when the dissolution profile of the dosage form meets the requirements for an immediate release dosage form

Waiver of In Vivo Bioequivalence Study based on

Pharmaceutical Dosage Form (Solutions)

Biopharmaceutics Classification System

Dose (Highest Strength should be tested)

BCS BIOWAIVER

Biowaiver for

Rapid and similar dissolution High solubility ampHigh permeability Wide therapeutic window Excipients used in dosage form used

previously in approved IR solid dosage forms

REQUEST FOR BIOWAIVERS

Data Supporting -

Rapid and Similar Dissolution

High Permeability

High Solubility

Limitations of BCS as a Predictor of Drug

DispositionΩ Permeability (90 absorption) is difficult to

determine and difficult to convince the regulatory agency

Ω There is little predictability for BCS classification drugs beyond Class 1 primarily due to the difficulty of determining and proving 90 absorption many drugs are misclassified (eg HIV protease inhibitors

as Class 4 compounds))

Conclusion BCS aims to provide a regulatory tool for

replacing certain BE studies by accurate in-vitro dissolution tests

This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in

drug molecules with a sufficiently high permeability solubility and dissolution

rate and that will automatically increase the importance of the BCS as

a regulatory tool over time

References Draft guidance for industry waiver of in vivo

bioavailability and bioequivalence studies for immediate release solid oral dosage forms containing certain active moieties active ingredients based on a biopharmaceutic classification system february 1999 CDERFDA

Amidon GL Lennernas H Shah VP Crison JRA A theoretical basis for a biopharmaceutic drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharm Res 12 413-420 (1995)

Guidance for industry immediate release solid oral dosage forms scale up and post approval changes november 1995 CDERFDA

Medicamento generico from website httpwwwAnvisaGo

Devane J Oral drug delivery technology addressing the solubility permeability paradigm pharm Technol 68-74 november 1998

Amidon G LLennernaumls H Shah V P And crisonj R A theoretical basis for a biopharmaceutics drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharmaceutical research 12 413-420 (1995)

Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA CDER 1997 1048603httpwwwfdagovcderguidance1713bp1pdf

Guidance for Industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System FDA CDER August 2000 httpwwwfdagovcderguidance3618fnlhtm

Thank you

• BIOPHARMACEUTICS CLASSIFICATION SYSTEM
• Contents
• Introduction
• Slide 4
• Slide 5
• Biopharmaceutics Classification System
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• DISSOLUTION DETERMINATION
• CLASS BOUNDARIES
• BCS Class Boundaries Objectives
• Slide 15
• BCS -Implications for drug development
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Applications of BCS in oral drug delivery technology
• Class II - High Permeability Low Solubility
• Slide 27
• Slide 28
• Biowaiver
• Waiver of In Vivo Bioequivalence Study based on
• BCS BIOWAIVER
• REQUEST FOR BIOWAIVERS
• Limitations of BCS as a Predictor of Drug Disposition
• Conclusion
• References
• Slide 36
• Slide 37

Introduction

Biopharmaceutics Classification System (BCS)

Scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability

What is the need for a classification based on

biopharmaceutics of the drugbull Ans Its importance in determining bioavailability

spadesRoute of choice for the formulators Continues to dominate the area of drug delivery

technologies

LIMITATIONS Absorption and Bioavailability in the milieu of

gastrointestinal tract Limitations more prominent

with the advent of protein and peptide drugs compounds emerging as a result of combinatorial chemistry and

the technique of high throughput screening

ORAL ROUTE

drug solubilitydrug product quality attributes

API structure salt form and

excipients

Bioavailability of drug is determined by

extent of drug solubility and

permeability

Guidance provided by the US Food and Drug Administration for predicting the intestinal drug

absorption

The fundamental basis established by

Dr Gordon Amidon Distinguished Science Award (Aug rsquo06 FIP)

First introduced into regulatory decision-making process in the guidance document on Immediate Release Solid Oral Dosage

Forms Scale Up And Post Approval Changes

Biopharmaceutics Classification System

Drug development tool that allows estimation of the contributions of 3 major factors that affect oral drug absorption from immediate release solid oral dosage forms

DissolutionSolubility

Intestinal permeability

The Biopharmaceutics Classification System (BCS)(as defined by the FDA after Amidon)

SIMILAR IN VIVO DISSOLUTION

SIMILAR IN VIVO ABSORPTION

SIMILAR SYSTEMIC AVAILABILITY

Dissolution of drug in vivo

Drug Concentration in the Membrane Domain

Intestinal Absorption

determines

proportional

Basis of BCS

(37plusmn100C in aqueous medium with pH range of 1-75)

A sufficient number of pH conditions ionization characteristics of the test drug substance

A minimum of three replicate determinations of solubility in each pH condition

Standard buffer solutions described in pharmacopoeias Methods other than shake flask method (with

Justification) e g acid or base titration methods

SOLUBILITY DETERMINATION

clubsNot just based on lipophilicity (encompass in vivo effects of efflux and uptake transporters)

A Human studies Mass balance studies Absolute bioavailability studies Intestinal perfusion methods

BIn vivo or in situ intestinal perfusion in a suitable animal model

CIn vitro permeability methods using excised intestinal tissues

D In vitro permeation studies across a monolayer of cultured epithelial cellseg Caco-2 cells or TC-7 cells

Determination of permeability

DISSOLUTION DETERMINATION

USP apparatus I (basket) at 100 rpm or USP apparatus II (paddle) at 50 rpm

Dissolution media (900 ml) 01 N HCl or simulated gastric fluid pH 45 buffer and pH 68 buffer or simulated intestinal fluid

Compare dissolution profiles of test and reference products using a similarity factor (f2)

0

CLASS BOUNDARIES

HIGHLY SOLUBLE the highest dose strength is soluble in lt 250 ml water over a pH range of 1 to 75

The volume estimate-a glassful (8 ounce)

HIGHLY PERMEABLE when the extent of absorption in humans is determined to be gt 90 of an administered dose

RAPIDLY DISSOLVING when gt 85 of the labeled amount of drug substance dissolves within 30 minutes using USP apparatus I or II in a volume of lt 900 ml buffer solutions

BCS Class Boundaries Objectives

Dissolution(Product)

Solubility (Drug)

Permeability

(Drug)

Rapid dissolution - ensure that in vivo dissolution is not likely to be theldquorate determiningrdquo step

High solubility- ensure that solubilityis not likely to limit dissolution and therefore absorption

High permeability - ensure that drugis completely absorbed during the limitedtransit time through the small intestine

BCS -Implications for drug developmentЖApplication in early drug development and then in

the management of product change through its life cycle

ЖAids fundamental understanding of the biopharmaceutical and physical properties of the drug

ЖAids discriminatory dissolution method development

ЖCan help guide the development of in-vitroin-vivo correlations

ЖCan be used to obtain a biowaiver

ЖDevelopment of poorly soluble drugs

This classification is associated with drug dissolution and absorption model which identifies the key parameters controlling drug absorption as a set of dimensionless numbers viz

BCS defines 3 numbers (no units)

An ~ absorption number Do ~ dose number Dn ~ dissolution number

ABS

GI

GI

eff

TT

TR

PAn

Effective permeability

Radius of GI

Residence time in GI

Time required forcomplete absorption

Absorption NumberA function of GI Permeability to Drug Substance

S

Water

CV

DDo

Highest Dose Unit

250 mL

Solubility

Dose NumberA function of solubility of drug substance

Solubility mgmL

DISS

GI

GI

S

TT

TC

rD

Dn2

3Diffusivity5x10-6 cm2s

Density12 mgcm3

Particle Radiusm

Residence time in GI 180 min

Time required forcomplete dissolution

Dissolution NumberA function of drug release from formulation

IVIVC expectations for immediate release products based on BCS

Class Solubility Permeability Absorption rate control

IVIVC expectations for Immediate release product

I High High Gastric emptying

IVIVC expected if dissolution rate is slower than gastric emptying rate otherwise limited or no correlations

II Low High Dissolution IVIVC expected if in vitro dissolution rate is similar to in vivo dissolution rate unless dose is very high

III High Low Permeability Absorption (permeability) is rate determining and limited or no IVIVC with dissolution

IV Low Low Case by case

Limited or no IVIVC is expected

High Solubility Low Solubility H

igh

Pe

rmea

bil

ity

Class 1 Abacavir Acetaminophen Acyclovirb AmilorideSI

Amitryptyline SI Antipyrine Atropine Buspironec Caffeine Captopril ChloroquineSI

Chlorpheniramine Cyclophosphamide Desipramine Diazepam Diltiazem SI Diphenhydramine Disopyramide Doxepin Doxycycline Enalapril Ephedrine Ergonovine Ethambutol Ethinyl Estradiol FluoxetineI

Glucose

ImipramineI Ketorolac Ketoprofen Labetolol LevodopaS Levofloxacin S LidocaineI Lomefloxacin Meperidine Metoprolol Metronidazole MidazolamSI Minocycline Misoprostol Nifedipine S Phenobarbital Phenylalanine Prednisolone PrimaquineS Promazine Propranolol I QuinidineSI Rosiglitazone Salicylic acid Theophylline Valproic acid Verapamil I Zidovudine

Class 2 Amiodarone I AtorvastatinS I AzithromycinS I

Carbamazepine SI Carvedilol Chlorpromazine I CisaprideS

Ciprofloxacin S Cyclosporine S I Danazol Dapsone Diclofenac Diflunisal Digoxin S Erythromycin SI Flurbiprofen Glipizide GlyburideSI Griseofulvin Ibuprofen Indinavir S

Indomethacin

Itraconazole SI Ketoconazole I LansoprazoleI Lovastatin SI Mebendazole Naproxen Nelfinavir SI Ofloxacin Oxaprozin Phenazopyridine PhenytoinS Piroxicam Raloxifene S Ritonavir SI Saquinavir SI Sirolimus S Spironolactone I Tacrolimus SI TalinololS

Tamoxifen I Terfenadine I Warfarin

High Solubility Low Solubility Lo

w P

erm

eabi

lity

Class 3 Acyclovir Amiloride SI Amoxicillin SI Atenolol Atropine Bisphosphonates Bidisomide Captopril Cefazolin Cetirizine Cimetidine S Ciprofloxacin S Cloxacillin Dicloxacillin S Erythromycin SI

Famotidine

Fexofenadine S Folinic acid Furosemide Ganciclovir Hydrochlorothiazide Lisinopril Metformin Methotrexate Nadolol Pravastatin S Penicillins Ranitidine S Tetracycline Trimethoprim S Valsartan Zalcitabine

Class 4 Amphotericin B Chlorthalidone Chlorothiazide Colistin Ciprofloxacin S Furosemide Hydrochlorothiazide Mebendazole Methotrexate Neomycin

Applications of BCS in oral drug delivery technology

Achieve a target release profile associated with a particular pharmacokinetic andor pharmacodynamic profile

Formulation approaches include both control of release rate and certain physicochemical properties of drugs like pH-solubility profile of drug

Class I - High Permeability High Solubility

Micronisation

Addition of surfactants

Formulation as emulsions and microemulsions systems

Use of complexing agents like cyclodextrins

Class II - High Permeability

Low Solubility

Require the technologies that address to fundamental limitations of absolute or regional permeability

Peptides and proteins constitute the part of class III and the technologies handling such materials are on rise now days

Class III - Low Permeability High Solubility

Class IV - Low Permeability Low Solubility

Major challenge for development of drug delivery system and the route of choice for administering such drugs is parenteral (solubility enhancers)

Fortunately extreme examples are the exception rather than the rule and are rarely developed and reach the market

Biowaiver A biowaiver is an exemption from

conducting human bioequivalence studies when the active ingredient(s) meet certain solubility and permeability criteria in vitro and when the dissolution profile of the dosage form meets the requirements for an immediate release dosage form

Waiver of In Vivo Bioequivalence Study based on

Pharmaceutical Dosage Form (Solutions)

Biopharmaceutics Classification System

Dose (Highest Strength should be tested)

BCS BIOWAIVER

Biowaiver for

Rapid and similar dissolution High solubility ampHigh permeability Wide therapeutic window Excipients used in dosage form used

previously in approved IR solid dosage forms

REQUEST FOR BIOWAIVERS

Data Supporting -

Rapid and Similar Dissolution

High Permeability

High Solubility

Limitations of BCS as a Predictor of Drug

DispositionΩ Permeability (90 absorption) is difficult to

determine and difficult to convince the regulatory agency

Ω There is little predictability for BCS classification drugs beyond Class 1 primarily due to the difficulty of determining and proving 90 absorption many drugs are misclassified (eg HIV protease inhibitors

as Class 4 compounds))

Conclusion BCS aims to provide a regulatory tool for

replacing certain BE studies by accurate in-vitro dissolution tests

This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in

drug molecules with a sufficiently high permeability solubility and dissolution

rate and that will automatically increase the importance of the BCS as

a regulatory tool over time

References Draft guidance for industry waiver of in vivo

bioavailability and bioequivalence studies for immediate release solid oral dosage forms containing certain active moieties active ingredients based on a biopharmaceutic classification system february 1999 CDERFDA

Amidon GL Lennernas H Shah VP Crison JRA A theoretical basis for a biopharmaceutic drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharm Res 12 413-420 (1995)

Guidance for industry immediate release solid oral dosage forms scale up and post approval changes november 1995 CDERFDA

Medicamento generico from website httpwwwAnvisaGo

Devane J Oral drug delivery technology addressing the solubility permeability paradigm pharm Technol 68-74 november 1998

Amidon G LLennernaumls H Shah V P And crisonj R A theoretical basis for a biopharmaceutics drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharmaceutical research 12 413-420 (1995)

Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA CDER 1997 1048603httpwwwfdagovcderguidance1713bp1pdf

Guidance for Industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System FDA CDER August 2000 httpwwwfdagovcderguidance3618fnlhtm

Thank you

• BIOPHARMACEUTICS CLASSIFICATION SYSTEM
• Contents
• Introduction
• Slide 4
• Slide 5
• Biopharmaceutics Classification System
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• DISSOLUTION DETERMINATION
• CLASS BOUNDARIES
• BCS Class Boundaries Objectives
• Slide 15
• BCS -Implications for drug development
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Applications of BCS in oral drug delivery technology
• Class II - High Permeability Low Solubility
• Slide 27
• Slide 28
• Biowaiver
• Waiver of In Vivo Bioequivalence Study based on
• BCS BIOWAIVER
• REQUEST FOR BIOWAIVERS
• Limitations of BCS as a Predictor of Drug Disposition
• Conclusion
• References
• Slide 36
• Slide 37

spadesRoute of choice for the formulators Continues to dominate the area of drug delivery

technologies

LIMITATIONS Absorption and Bioavailability in the milieu of

gastrointestinal tract Limitations more prominent

with the advent of protein and peptide drugs compounds emerging as a result of combinatorial chemistry and

the technique of high throughput screening

ORAL ROUTE

drug solubilitydrug product quality attributes

API structure salt form and

excipients

Bioavailability of drug is determined by

extent of drug solubility and

permeability

Guidance provided by the US Food and Drug Administration for predicting the intestinal drug

absorption

The fundamental basis established by

Dr Gordon Amidon Distinguished Science Award (Aug rsquo06 FIP)

First introduced into regulatory decision-making process in the guidance document on Immediate Release Solid Oral Dosage

Forms Scale Up And Post Approval Changes

Biopharmaceutics Classification System

Drug development tool that allows estimation of the contributions of 3 major factors that affect oral drug absorption from immediate release solid oral dosage forms

DissolutionSolubility

Intestinal permeability

The Biopharmaceutics Classification System (BCS)(as defined by the FDA after Amidon)

SIMILAR IN VIVO DISSOLUTION

SIMILAR IN VIVO ABSORPTION

SIMILAR SYSTEMIC AVAILABILITY

Dissolution of drug in vivo

Drug Concentration in the Membrane Domain

Intestinal Absorption

determines

proportional

Basis of BCS

(37plusmn100C in aqueous medium with pH range of 1-75)

A sufficient number of pH conditions ionization characteristics of the test drug substance

A minimum of three replicate determinations of solubility in each pH condition

Standard buffer solutions described in pharmacopoeias Methods other than shake flask method (with

Justification) e g acid or base titration methods

SOLUBILITY DETERMINATION

clubsNot just based on lipophilicity (encompass in vivo effects of efflux and uptake transporters)

A Human studies Mass balance studies Absolute bioavailability studies Intestinal perfusion methods

BIn vivo or in situ intestinal perfusion in a suitable animal model

CIn vitro permeability methods using excised intestinal tissues

D In vitro permeation studies across a monolayer of cultured epithelial cellseg Caco-2 cells or TC-7 cells

Determination of permeability

DISSOLUTION DETERMINATION

USP apparatus I (basket) at 100 rpm or USP apparatus II (paddle) at 50 rpm

Dissolution media (900 ml) 01 N HCl or simulated gastric fluid pH 45 buffer and pH 68 buffer or simulated intestinal fluid

Compare dissolution profiles of test and reference products using a similarity factor (f2)

0

CLASS BOUNDARIES

HIGHLY SOLUBLE the highest dose strength is soluble in lt 250 ml water over a pH range of 1 to 75

The volume estimate-a glassful (8 ounce)

HIGHLY PERMEABLE when the extent of absorption in humans is determined to be gt 90 of an administered dose

RAPIDLY DISSOLVING when gt 85 of the labeled amount of drug substance dissolves within 30 minutes using USP apparatus I or II in a volume of lt 900 ml buffer solutions

BCS Class Boundaries Objectives

Dissolution(Product)

Solubility (Drug)

Permeability

(Drug)

Rapid dissolution - ensure that in vivo dissolution is not likely to be theldquorate determiningrdquo step

High solubility- ensure that solubilityis not likely to limit dissolution and therefore absorption

High permeability - ensure that drugis completely absorbed during the limitedtransit time through the small intestine

BCS -Implications for drug developmentЖApplication in early drug development and then in

the management of product change through its life cycle

ЖAids fundamental understanding of the biopharmaceutical and physical properties of the drug

ЖAids discriminatory dissolution method development

ЖCan help guide the development of in-vitroin-vivo correlations

ЖCan be used to obtain a biowaiver

ЖDevelopment of poorly soluble drugs

This classification is associated with drug dissolution and absorption model which identifies the key parameters controlling drug absorption as a set of dimensionless numbers viz

BCS defines 3 numbers (no units)

An ~ absorption number Do ~ dose number Dn ~ dissolution number

ABS

GI

GI

eff

TT

TR

PAn

Effective permeability

Radius of GI

Residence time in GI

Time required forcomplete absorption

Absorption NumberA function of GI Permeability to Drug Substance

S

Water

CV

DDo

Highest Dose Unit

250 mL

Solubility

Dose NumberA function of solubility of drug substance

Solubility mgmL

DISS

GI

GI

S

TT

TC

rD

Dn2

3Diffusivity5x10-6 cm2s

Density12 mgcm3

Particle Radiusm

Residence time in GI 180 min

Time required forcomplete dissolution

Dissolution NumberA function of drug release from formulation

IVIVC expectations for immediate release products based on BCS

Class Solubility Permeability Absorption rate control

IVIVC expectations for Immediate release product

I High High Gastric emptying

IVIVC expected if dissolution rate is slower than gastric emptying rate otherwise limited or no correlations

II Low High Dissolution IVIVC expected if in vitro dissolution rate is similar to in vivo dissolution rate unless dose is very high

III High Low Permeability Absorption (permeability) is rate determining and limited or no IVIVC with dissolution

IV Low Low Case by case

Limited or no IVIVC is expected

High Solubility Low Solubility H

igh

Pe

rmea

bil

ity

Class 1 Abacavir Acetaminophen Acyclovirb AmilorideSI

Amitryptyline SI Antipyrine Atropine Buspironec Caffeine Captopril ChloroquineSI

Chlorpheniramine Cyclophosphamide Desipramine Diazepam Diltiazem SI Diphenhydramine Disopyramide Doxepin Doxycycline Enalapril Ephedrine Ergonovine Ethambutol Ethinyl Estradiol FluoxetineI

Glucose

ImipramineI Ketorolac Ketoprofen Labetolol LevodopaS Levofloxacin S LidocaineI Lomefloxacin Meperidine Metoprolol Metronidazole MidazolamSI Minocycline Misoprostol Nifedipine S Phenobarbital Phenylalanine Prednisolone PrimaquineS Promazine Propranolol I QuinidineSI Rosiglitazone Salicylic acid Theophylline Valproic acid Verapamil I Zidovudine

Class 2 Amiodarone I AtorvastatinS I AzithromycinS I

Carbamazepine SI Carvedilol Chlorpromazine I CisaprideS

Ciprofloxacin S Cyclosporine S I Danazol Dapsone Diclofenac Diflunisal Digoxin S Erythromycin SI Flurbiprofen Glipizide GlyburideSI Griseofulvin Ibuprofen Indinavir S

Indomethacin

Itraconazole SI Ketoconazole I LansoprazoleI Lovastatin SI Mebendazole Naproxen Nelfinavir SI Ofloxacin Oxaprozin Phenazopyridine PhenytoinS Piroxicam Raloxifene S Ritonavir SI Saquinavir SI Sirolimus S Spironolactone I Tacrolimus SI TalinololS

Tamoxifen I Terfenadine I Warfarin

High Solubility Low Solubility Lo

w P

erm

eabi

lity

Class 3 Acyclovir Amiloride SI Amoxicillin SI Atenolol Atropine Bisphosphonates Bidisomide Captopril Cefazolin Cetirizine Cimetidine S Ciprofloxacin S Cloxacillin Dicloxacillin S Erythromycin SI

Famotidine

Fexofenadine S Folinic acid Furosemide Ganciclovir Hydrochlorothiazide Lisinopril Metformin Methotrexate Nadolol Pravastatin S Penicillins Ranitidine S Tetracycline Trimethoprim S Valsartan Zalcitabine

Class 4 Amphotericin B Chlorthalidone Chlorothiazide Colistin Ciprofloxacin S Furosemide Hydrochlorothiazide Mebendazole Methotrexate Neomycin

Applications of BCS in oral drug delivery technology

Achieve a target release profile associated with a particular pharmacokinetic andor pharmacodynamic profile

Formulation approaches include both control of release rate and certain physicochemical properties of drugs like pH-solubility profile of drug

Class I - High Permeability High Solubility

Micronisation

Addition of surfactants

Formulation as emulsions and microemulsions systems

Use of complexing agents like cyclodextrins

Class II - High Permeability

Low Solubility

Require the technologies that address to fundamental limitations of absolute or regional permeability

Peptides and proteins constitute the part of class III and the technologies handling such materials are on rise now days

Class III - Low Permeability High Solubility

Class IV - Low Permeability Low Solubility

Major challenge for development of drug delivery system and the route of choice for administering such drugs is parenteral (solubility enhancers)

Fortunately extreme examples are the exception rather than the rule and are rarely developed and reach the market

Biowaiver A biowaiver is an exemption from

conducting human bioequivalence studies when the active ingredient(s) meet certain solubility and permeability criteria in vitro and when the dissolution profile of the dosage form meets the requirements for an immediate release dosage form

Waiver of In Vivo Bioequivalence Study based on

Pharmaceutical Dosage Form (Solutions)

Biopharmaceutics Classification System

Dose (Highest Strength should be tested)

BCS BIOWAIVER

Biowaiver for

Rapid and similar dissolution High solubility ampHigh permeability Wide therapeutic window Excipients used in dosage form used

previously in approved IR solid dosage forms

REQUEST FOR BIOWAIVERS

Data Supporting -

Rapid and Similar Dissolution

High Permeability

High Solubility

Limitations of BCS as a Predictor of Drug

DispositionΩ Permeability (90 absorption) is difficult to

determine and difficult to convince the regulatory agency

Ω There is little predictability for BCS classification drugs beyond Class 1 primarily due to the difficulty of determining and proving 90 absorption many drugs are misclassified (eg HIV protease inhibitors

as Class 4 compounds))

Conclusion BCS aims to provide a regulatory tool for

replacing certain BE studies by accurate in-vitro dissolution tests

This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in

drug molecules with a sufficiently high permeability solubility and dissolution

rate and that will automatically increase the importance of the BCS as

a regulatory tool over time

References Draft guidance for industry waiver of in vivo

bioavailability and bioequivalence studies for immediate release solid oral dosage forms containing certain active moieties active ingredients based on a biopharmaceutic classification system february 1999 CDERFDA

Amidon GL Lennernas H Shah VP Crison JRA A theoretical basis for a biopharmaceutic drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharm Res 12 413-420 (1995)

Guidance for industry immediate release solid oral dosage forms scale up and post approval changes november 1995 CDERFDA

Medicamento generico from website httpwwwAnvisaGo

Devane J Oral drug delivery technology addressing the solubility permeability paradigm pharm Technol 68-74 november 1998

Amidon G LLennernaumls H Shah V P And crisonj R A theoretical basis for a biopharmaceutics drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharmaceutical research 12 413-420 (1995)

Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA CDER 1997 1048603httpwwwfdagovcderguidance1713bp1pdf

Guidance for Industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System FDA CDER August 2000 httpwwwfdagovcderguidance3618fnlhtm

Thank you

• BIOPHARMACEUTICS CLASSIFICATION SYSTEM
• Contents
• Introduction
• Slide 4
• Slide 5
• Biopharmaceutics Classification System
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• DISSOLUTION DETERMINATION
• CLASS BOUNDARIES
• BCS Class Boundaries Objectives
• Slide 15
• BCS -Implications for drug development
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Applications of BCS in oral drug delivery technology
• Class II - High Permeability Low Solubility
• Slide 27
• Slide 28
• Biowaiver
• Waiver of In Vivo Bioequivalence Study based on
• BCS BIOWAIVER
• REQUEST FOR BIOWAIVERS
• Limitations of BCS as a Predictor of Drug Disposition
• Conclusion
• References
• Slide 36
• Slide 37

drug solubilitydrug product quality attributes

API structure salt form and

excipients

Bioavailability of drug is determined by

extent of drug solubility and

permeability

Guidance provided by the US Food and Drug Administration for predicting the intestinal drug

absorption

The fundamental basis established by

Dr Gordon Amidon Distinguished Science Award (Aug rsquo06 FIP)

First introduced into regulatory decision-making process in the guidance document on Immediate Release Solid Oral Dosage

Forms Scale Up And Post Approval Changes

Biopharmaceutics Classification System

Drug development tool that allows estimation of the contributions of 3 major factors that affect oral drug absorption from immediate release solid oral dosage forms

DissolutionSolubility

Intestinal permeability

The Biopharmaceutics Classification System (BCS)(as defined by the FDA after Amidon)

SIMILAR IN VIVO DISSOLUTION

SIMILAR IN VIVO ABSORPTION

SIMILAR SYSTEMIC AVAILABILITY

Dissolution of drug in vivo

Drug Concentration in the Membrane Domain

Intestinal Absorption

determines

proportional

Basis of BCS

(37plusmn100C in aqueous medium with pH range of 1-75)

A sufficient number of pH conditions ionization characteristics of the test drug substance

A minimum of three replicate determinations of solubility in each pH condition

Standard buffer solutions described in pharmacopoeias Methods other than shake flask method (with

Justification) e g acid or base titration methods

SOLUBILITY DETERMINATION

clubsNot just based on lipophilicity (encompass in vivo effects of efflux and uptake transporters)

A Human studies Mass balance studies Absolute bioavailability studies Intestinal perfusion methods

BIn vivo or in situ intestinal perfusion in a suitable animal model

CIn vitro permeability methods using excised intestinal tissues

D In vitro permeation studies across a monolayer of cultured epithelial cellseg Caco-2 cells or TC-7 cells

Determination of permeability

DISSOLUTION DETERMINATION

USP apparatus I (basket) at 100 rpm or USP apparatus II (paddle) at 50 rpm

Dissolution media (900 ml) 01 N HCl or simulated gastric fluid pH 45 buffer and pH 68 buffer or simulated intestinal fluid

Compare dissolution profiles of test and reference products using a similarity factor (f2)

0

CLASS BOUNDARIES

HIGHLY SOLUBLE the highest dose strength is soluble in lt 250 ml water over a pH range of 1 to 75

The volume estimate-a glassful (8 ounce)

HIGHLY PERMEABLE when the extent of absorption in humans is determined to be gt 90 of an administered dose

RAPIDLY DISSOLVING when gt 85 of the labeled amount of drug substance dissolves within 30 minutes using USP apparatus I or II in a volume of lt 900 ml buffer solutions

BCS Class Boundaries Objectives

Dissolution(Product)

Solubility (Drug)

Permeability

(Drug)

Rapid dissolution - ensure that in vivo dissolution is not likely to be theldquorate determiningrdquo step

High solubility- ensure that solubilityis not likely to limit dissolution and therefore absorption

High permeability - ensure that drugis completely absorbed during the limitedtransit time through the small intestine

BCS -Implications for drug developmentЖApplication in early drug development and then in

the management of product change through its life cycle

ЖAids fundamental understanding of the biopharmaceutical and physical properties of the drug

ЖAids discriminatory dissolution method development

ЖCan help guide the development of in-vitroin-vivo correlations

ЖCan be used to obtain a biowaiver

ЖDevelopment of poorly soluble drugs

This classification is associated with drug dissolution and absorption model which identifies the key parameters controlling drug absorption as a set of dimensionless numbers viz

BCS defines 3 numbers (no units)

An ~ absorption number Do ~ dose number Dn ~ dissolution number

ABS

GI

GI

eff

TT

TR

PAn

Effective permeability

Radius of GI

Residence time in GI

Time required forcomplete absorption

Absorption NumberA function of GI Permeability to Drug Substance

S

Water

CV

DDo

Highest Dose Unit

250 mL

Solubility

Dose NumberA function of solubility of drug substance

Solubility mgmL

DISS

GI

GI

S

TT

TC

rD

Dn2

3Diffusivity5x10-6 cm2s

Density12 mgcm3

Particle Radiusm

Residence time in GI 180 min

Time required forcomplete dissolution

Dissolution NumberA function of drug release from formulation

IVIVC expectations for immediate release products based on BCS

Class Solubility Permeability Absorption rate control

IVIVC expectations for Immediate release product

I High High Gastric emptying

IVIVC expected if dissolution rate is slower than gastric emptying rate otherwise limited or no correlations

II Low High Dissolution IVIVC expected if in vitro dissolution rate is similar to in vivo dissolution rate unless dose is very high

III High Low Permeability Absorption (permeability) is rate determining and limited or no IVIVC with dissolution

IV Low Low Case by case

Limited or no IVIVC is expected

High Solubility Low Solubility H

igh

Pe

rmea

bil

ity

Class 1 Abacavir Acetaminophen Acyclovirb AmilorideSI

Amitryptyline SI Antipyrine Atropine Buspironec Caffeine Captopril ChloroquineSI

Chlorpheniramine Cyclophosphamide Desipramine Diazepam Diltiazem SI Diphenhydramine Disopyramide Doxepin Doxycycline Enalapril Ephedrine Ergonovine Ethambutol Ethinyl Estradiol FluoxetineI

Glucose

ImipramineI Ketorolac Ketoprofen Labetolol LevodopaS Levofloxacin S LidocaineI Lomefloxacin Meperidine Metoprolol Metronidazole MidazolamSI Minocycline Misoprostol Nifedipine S Phenobarbital Phenylalanine Prednisolone PrimaquineS Promazine Propranolol I QuinidineSI Rosiglitazone Salicylic acid Theophylline Valproic acid Verapamil I Zidovudine

Class 2 Amiodarone I AtorvastatinS I AzithromycinS I

Carbamazepine SI Carvedilol Chlorpromazine I CisaprideS

Ciprofloxacin S Cyclosporine S I Danazol Dapsone Diclofenac Diflunisal Digoxin S Erythromycin SI Flurbiprofen Glipizide GlyburideSI Griseofulvin Ibuprofen Indinavir S

Indomethacin

Itraconazole SI Ketoconazole I LansoprazoleI Lovastatin SI Mebendazole Naproxen Nelfinavir SI Ofloxacin Oxaprozin Phenazopyridine PhenytoinS Piroxicam Raloxifene S Ritonavir SI Saquinavir SI Sirolimus S Spironolactone I Tacrolimus SI TalinololS

Tamoxifen I Terfenadine I Warfarin

High Solubility Low Solubility Lo

w P

erm

eabi

lity

Class 3 Acyclovir Amiloride SI Amoxicillin SI Atenolol Atropine Bisphosphonates Bidisomide Captopril Cefazolin Cetirizine Cimetidine S Ciprofloxacin S Cloxacillin Dicloxacillin S Erythromycin SI

Famotidine

Fexofenadine S Folinic acid Furosemide Ganciclovir Hydrochlorothiazide Lisinopril Metformin Methotrexate Nadolol Pravastatin S Penicillins Ranitidine S Tetracycline Trimethoprim S Valsartan Zalcitabine

Class 4 Amphotericin B Chlorthalidone Chlorothiazide Colistin Ciprofloxacin S Furosemide Hydrochlorothiazide Mebendazole Methotrexate Neomycin

Applications of BCS in oral drug delivery technology

Achieve a target release profile associated with a particular pharmacokinetic andor pharmacodynamic profile

Formulation approaches include both control of release rate and certain physicochemical properties of drugs like pH-solubility profile of drug

Class I - High Permeability High Solubility

Micronisation

Addition of surfactants

Formulation as emulsions and microemulsions systems

Use of complexing agents like cyclodextrins

Class II - High Permeability

Low Solubility

Require the technologies that address to fundamental limitations of absolute or regional permeability

Peptides and proteins constitute the part of class III and the technologies handling such materials are on rise now days

Class III - Low Permeability High Solubility

Class IV - Low Permeability Low Solubility

Major challenge for development of drug delivery system and the route of choice for administering such drugs is parenteral (solubility enhancers)

Fortunately extreme examples are the exception rather than the rule and are rarely developed and reach the market

Biowaiver A biowaiver is an exemption from

conducting human bioequivalence studies when the active ingredient(s) meet certain solubility and permeability criteria in vitro and when the dissolution profile of the dosage form meets the requirements for an immediate release dosage form

Waiver of In Vivo Bioequivalence Study based on

Pharmaceutical Dosage Form (Solutions)

Biopharmaceutics Classification System

Dose (Highest Strength should be tested)

BCS BIOWAIVER

Biowaiver for

Rapid and similar dissolution High solubility ampHigh permeability Wide therapeutic window Excipients used in dosage form used

previously in approved IR solid dosage forms

REQUEST FOR BIOWAIVERS

Data Supporting -

Rapid and Similar Dissolution

High Permeability

High Solubility

Limitations of BCS as a Predictor of Drug

DispositionΩ Permeability (90 absorption) is difficult to

determine and difficult to convince the regulatory agency

Ω There is little predictability for BCS classification drugs beyond Class 1 primarily due to the difficulty of determining and proving 90 absorption many drugs are misclassified (eg HIV protease inhibitors

as Class 4 compounds))

Conclusion BCS aims to provide a regulatory tool for

replacing certain BE studies by accurate in-vitro dissolution tests

This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in

drug molecules with a sufficiently high permeability solubility and dissolution

rate and that will automatically increase the importance of the BCS as

a regulatory tool over time

References Draft guidance for industry waiver of in vivo

bioavailability and bioequivalence studies for immediate release solid oral dosage forms containing certain active moieties active ingredients based on a biopharmaceutic classification system february 1999 CDERFDA

Amidon GL Lennernas H Shah VP Crison JRA A theoretical basis for a biopharmaceutic drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharm Res 12 413-420 (1995)

Guidance for industry immediate release solid oral dosage forms scale up and post approval changes november 1995 CDERFDA

Medicamento generico from website httpwwwAnvisaGo

Devane J Oral drug delivery technology addressing the solubility permeability paradigm pharm Technol 68-74 november 1998

Amidon G LLennernaumls H Shah V P And crisonj R A theoretical basis for a biopharmaceutics drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharmaceutical research 12 413-420 (1995)

Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA CDER 1997 1048603httpwwwfdagovcderguidance1713bp1pdf

Guidance for Industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System FDA CDER August 2000 httpwwwfdagovcderguidance3618fnlhtm

Thank you

• BIOPHARMACEUTICS CLASSIFICATION SYSTEM
• Contents
• Introduction
• Slide 4
• Slide 5
• Biopharmaceutics Classification System
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• DISSOLUTION DETERMINATION
• CLASS BOUNDARIES
• BCS Class Boundaries Objectives
• Slide 15
• BCS -Implications for drug development
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Applications of BCS in oral drug delivery technology
• Class II - High Permeability Low Solubility
• Slide 27
• Slide 28
• Biowaiver
• Waiver of In Vivo Bioequivalence Study based on
• BCS BIOWAIVER
• REQUEST FOR BIOWAIVERS
• Limitations of BCS as a Predictor of Drug Disposition
• Conclusion
• References
• Slide 36
• Slide 37

Guidance provided by the US Food and Drug Administration for predicting the intestinal drug

absorption

The fundamental basis established by

Dr Gordon Amidon Distinguished Science Award (Aug rsquo06 FIP)

First introduced into regulatory decision-making process in the guidance document on Immediate Release Solid Oral Dosage

Forms Scale Up And Post Approval Changes

Biopharmaceutics Classification System

Drug development tool that allows estimation of the contributions of 3 major factors that affect oral drug absorption from immediate release solid oral dosage forms

DissolutionSolubility

Intestinal permeability

The Biopharmaceutics Classification System (BCS)(as defined by the FDA after Amidon)

SIMILAR IN VIVO DISSOLUTION

SIMILAR IN VIVO ABSORPTION

SIMILAR SYSTEMIC AVAILABILITY

Dissolution of drug in vivo

Drug Concentration in the Membrane Domain

Intestinal Absorption

determines

proportional

Basis of BCS

(37plusmn100C in aqueous medium with pH range of 1-75)

A sufficient number of pH conditions ionization characteristics of the test drug substance

A minimum of three replicate determinations of solubility in each pH condition

Standard buffer solutions described in pharmacopoeias Methods other than shake flask method (with

Justification) e g acid or base titration methods

SOLUBILITY DETERMINATION

clubsNot just based on lipophilicity (encompass in vivo effects of efflux and uptake transporters)

A Human studies Mass balance studies Absolute bioavailability studies Intestinal perfusion methods

BIn vivo or in situ intestinal perfusion in a suitable animal model

CIn vitro permeability methods using excised intestinal tissues

D In vitro permeation studies across a monolayer of cultured epithelial cellseg Caco-2 cells or TC-7 cells

Determination of permeability

DISSOLUTION DETERMINATION

USP apparatus I (basket) at 100 rpm or USP apparatus II (paddle) at 50 rpm

Dissolution media (900 ml) 01 N HCl or simulated gastric fluid pH 45 buffer and pH 68 buffer or simulated intestinal fluid

Compare dissolution profiles of test and reference products using a similarity factor (f2)

0

CLASS BOUNDARIES

HIGHLY SOLUBLE the highest dose strength is soluble in lt 250 ml water over a pH range of 1 to 75

The volume estimate-a glassful (8 ounce)

HIGHLY PERMEABLE when the extent of absorption in humans is determined to be gt 90 of an administered dose

RAPIDLY DISSOLVING when gt 85 of the labeled amount of drug substance dissolves within 30 minutes using USP apparatus I or II in a volume of lt 900 ml buffer solutions

BCS Class Boundaries Objectives

Dissolution(Product)

Solubility (Drug)

Permeability

(Drug)

Rapid dissolution - ensure that in vivo dissolution is not likely to be theldquorate determiningrdquo step

High solubility- ensure that solubilityis not likely to limit dissolution and therefore absorption

High permeability - ensure that drugis completely absorbed during the limitedtransit time through the small intestine

BCS -Implications for drug developmentЖApplication in early drug development and then in

the management of product change through its life cycle

ЖAids fundamental understanding of the biopharmaceutical and physical properties of the drug

ЖAids discriminatory dissolution method development

ЖCan help guide the development of in-vitroin-vivo correlations

ЖCan be used to obtain a biowaiver

ЖDevelopment of poorly soluble drugs

This classification is associated with drug dissolution and absorption model which identifies the key parameters controlling drug absorption as a set of dimensionless numbers viz

BCS defines 3 numbers (no units)

An ~ absorption number Do ~ dose number Dn ~ dissolution number

ABS

GI

GI

eff

TT

TR

PAn

Effective permeability

Radius of GI

Residence time in GI

Time required forcomplete absorption

Absorption NumberA function of GI Permeability to Drug Substance

S

Water

CV

DDo

Highest Dose Unit

250 mL

Solubility

Dose NumberA function of solubility of drug substance

Solubility mgmL

DISS

GI

GI

S

TT

TC

rD

Dn2

3Diffusivity5x10-6 cm2s

Density12 mgcm3

Particle Radiusm

Residence time in GI 180 min

Time required forcomplete dissolution

Dissolution NumberA function of drug release from formulation

IVIVC expectations for immediate release products based on BCS

Class Solubility Permeability Absorption rate control

IVIVC expectations for Immediate release product

I High High Gastric emptying

IVIVC expected if dissolution rate is slower than gastric emptying rate otherwise limited or no correlations

II Low High Dissolution IVIVC expected if in vitro dissolution rate is similar to in vivo dissolution rate unless dose is very high

III High Low Permeability Absorption (permeability) is rate determining and limited or no IVIVC with dissolution

IV Low Low Case by case

Limited or no IVIVC is expected

High Solubility Low Solubility H

igh

Pe

rmea

bil

ity

Class 1 Abacavir Acetaminophen Acyclovirb AmilorideSI

Amitryptyline SI Antipyrine Atropine Buspironec Caffeine Captopril ChloroquineSI

Chlorpheniramine Cyclophosphamide Desipramine Diazepam Diltiazem SI Diphenhydramine Disopyramide Doxepin Doxycycline Enalapril Ephedrine Ergonovine Ethambutol Ethinyl Estradiol FluoxetineI

Glucose

ImipramineI Ketorolac Ketoprofen Labetolol LevodopaS Levofloxacin S LidocaineI Lomefloxacin Meperidine Metoprolol Metronidazole MidazolamSI Minocycline Misoprostol Nifedipine S Phenobarbital Phenylalanine Prednisolone PrimaquineS Promazine Propranolol I QuinidineSI Rosiglitazone Salicylic acid Theophylline Valproic acid Verapamil I Zidovudine

Class 2 Amiodarone I AtorvastatinS I AzithromycinS I

Carbamazepine SI Carvedilol Chlorpromazine I CisaprideS

Ciprofloxacin S Cyclosporine S I Danazol Dapsone Diclofenac Diflunisal Digoxin S Erythromycin SI Flurbiprofen Glipizide GlyburideSI Griseofulvin Ibuprofen Indinavir S

Indomethacin

Itraconazole SI Ketoconazole I LansoprazoleI Lovastatin SI Mebendazole Naproxen Nelfinavir SI Ofloxacin Oxaprozin Phenazopyridine PhenytoinS Piroxicam Raloxifene S Ritonavir SI Saquinavir SI Sirolimus S Spironolactone I Tacrolimus SI TalinololS

Tamoxifen I Terfenadine I Warfarin

High Solubility Low Solubility Lo

w P

erm

eabi

lity

Class 3 Acyclovir Amiloride SI Amoxicillin SI Atenolol Atropine Bisphosphonates Bidisomide Captopril Cefazolin Cetirizine Cimetidine S Ciprofloxacin S Cloxacillin Dicloxacillin S Erythromycin SI

Famotidine

Fexofenadine S Folinic acid Furosemide Ganciclovir Hydrochlorothiazide Lisinopril Metformin Methotrexate Nadolol Pravastatin S Penicillins Ranitidine S Tetracycline Trimethoprim S Valsartan Zalcitabine

Class 4 Amphotericin B Chlorthalidone Chlorothiazide Colistin Ciprofloxacin S Furosemide Hydrochlorothiazide Mebendazole Methotrexate Neomycin

Applications of BCS in oral drug delivery technology

Achieve a target release profile associated with a particular pharmacokinetic andor pharmacodynamic profile

Formulation approaches include both control of release rate and certain physicochemical properties of drugs like pH-solubility profile of drug

Class I - High Permeability High Solubility

Micronisation

Addition of surfactants

Formulation as emulsions and microemulsions systems

Use of complexing agents like cyclodextrins

Class II - High Permeability

Low Solubility

Require the technologies that address to fundamental limitations of absolute or regional permeability

Peptides and proteins constitute the part of class III and the technologies handling such materials are on rise now days

Class III - Low Permeability High Solubility

Class IV - Low Permeability Low Solubility

Major challenge for development of drug delivery system and the route of choice for administering such drugs is parenteral (solubility enhancers)

Fortunately extreme examples are the exception rather than the rule and are rarely developed and reach the market

Biowaiver A biowaiver is an exemption from

conducting human bioequivalence studies when the active ingredient(s) meet certain solubility and permeability criteria in vitro and when the dissolution profile of the dosage form meets the requirements for an immediate release dosage form

Waiver of In Vivo Bioequivalence Study based on

Pharmaceutical Dosage Form (Solutions)

Biopharmaceutics Classification System

Dose (Highest Strength should be tested)

BCS BIOWAIVER

Biowaiver for

Rapid and similar dissolution High solubility ampHigh permeability Wide therapeutic window Excipients used in dosage form used

previously in approved IR solid dosage forms

REQUEST FOR BIOWAIVERS

Data Supporting -

Rapid and Similar Dissolution

High Permeability

High Solubility

Limitations of BCS as a Predictor of Drug

DispositionΩ Permeability (90 absorption) is difficult to

determine and difficult to convince the regulatory agency

Ω There is little predictability for BCS classification drugs beyond Class 1 primarily due to the difficulty of determining and proving 90 absorption many drugs are misclassified (eg HIV protease inhibitors

as Class 4 compounds))

Conclusion BCS aims to provide a regulatory tool for

replacing certain BE studies by accurate in-vitro dissolution tests

This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in

drug molecules with a sufficiently high permeability solubility and dissolution

rate and that will automatically increase the importance of the BCS as

a regulatory tool over time

References Draft guidance for industry waiver of in vivo

bioavailability and bioequivalence studies for immediate release solid oral dosage forms containing certain active moieties active ingredients based on a biopharmaceutic classification system february 1999 CDERFDA

Amidon GL Lennernas H Shah VP Crison JRA A theoretical basis for a biopharmaceutic drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharm Res 12 413-420 (1995)

Guidance for industry immediate release solid oral dosage forms scale up and post approval changes november 1995 CDERFDA

Medicamento generico from website httpwwwAnvisaGo

Devane J Oral drug delivery technology addressing the solubility permeability paradigm pharm Technol 68-74 november 1998

Amidon G LLennernaumls H Shah V P And crisonj R A theoretical basis for a biopharmaceutics drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharmaceutical research 12 413-420 (1995)

Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA CDER 1997 1048603httpwwwfdagovcderguidance1713bp1pdf

Guidance for Industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System FDA CDER August 2000 httpwwwfdagovcderguidance3618fnlhtm

Thank you

• BIOPHARMACEUTICS CLASSIFICATION SYSTEM
• Contents
• Introduction
• Slide 4
• Slide 5
• Biopharmaceutics Classification System
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• DISSOLUTION DETERMINATION
• CLASS BOUNDARIES
• BCS Class Boundaries Objectives
• Slide 15
• BCS -Implications for drug development
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Applications of BCS in oral drug delivery technology
• Class II - High Permeability Low Solubility
• Slide 27
• Slide 28
• Biowaiver
• Waiver of In Vivo Bioequivalence Study based on
• BCS BIOWAIVER
• REQUEST FOR BIOWAIVERS
• Limitations of BCS as a Predictor of Drug Disposition
• Conclusion
• References
• Slide 36
• Slide 37

Drug development tool that allows estimation of the contributions of 3 major factors that affect oral drug absorption from immediate release solid oral dosage forms

DissolutionSolubility

Intestinal permeability

The Biopharmaceutics Classification System (BCS)(as defined by the FDA after Amidon)

SIMILAR IN VIVO DISSOLUTION

SIMILAR IN VIVO ABSORPTION

SIMILAR SYSTEMIC AVAILABILITY

Dissolution of drug in vivo

Drug Concentration in the Membrane Domain

Intestinal Absorption

determines

proportional

Basis of BCS

(37plusmn100C in aqueous medium with pH range of 1-75)

A sufficient number of pH conditions ionization characteristics of the test drug substance

A minimum of three replicate determinations of solubility in each pH condition

Standard buffer solutions described in pharmacopoeias Methods other than shake flask method (with

Justification) e g acid or base titration methods

SOLUBILITY DETERMINATION

clubsNot just based on lipophilicity (encompass in vivo effects of efflux and uptake transporters)

A Human studies Mass balance studies Absolute bioavailability studies Intestinal perfusion methods

BIn vivo or in situ intestinal perfusion in a suitable animal model

CIn vitro permeability methods using excised intestinal tissues

D In vitro permeation studies across a monolayer of cultured epithelial cellseg Caco-2 cells or TC-7 cells

Determination of permeability

DISSOLUTION DETERMINATION

USP apparatus I (basket) at 100 rpm or USP apparatus II (paddle) at 50 rpm

Dissolution media (900 ml) 01 N HCl or simulated gastric fluid pH 45 buffer and pH 68 buffer or simulated intestinal fluid

Compare dissolution profiles of test and reference products using a similarity factor (f2)

0

CLASS BOUNDARIES

HIGHLY SOLUBLE the highest dose strength is soluble in lt 250 ml water over a pH range of 1 to 75

The volume estimate-a glassful (8 ounce)

HIGHLY PERMEABLE when the extent of absorption in humans is determined to be gt 90 of an administered dose

RAPIDLY DISSOLVING when gt 85 of the labeled amount of drug substance dissolves within 30 minutes using USP apparatus I or II in a volume of lt 900 ml buffer solutions

BCS Class Boundaries Objectives

Dissolution(Product)

Solubility (Drug)

Permeability

(Drug)

Rapid dissolution - ensure that in vivo dissolution is not likely to be theldquorate determiningrdquo step

High solubility- ensure that solubilityis not likely to limit dissolution and therefore absorption

High permeability - ensure that drugis completely absorbed during the limitedtransit time through the small intestine

BCS -Implications for drug developmentЖApplication in early drug development and then in

the management of product change through its life cycle

ЖAids fundamental understanding of the biopharmaceutical and physical properties of the drug

ЖAids discriminatory dissolution method development

ЖCan help guide the development of in-vitroin-vivo correlations

ЖCan be used to obtain a biowaiver

ЖDevelopment of poorly soluble drugs

This classification is associated with drug dissolution and absorption model which identifies the key parameters controlling drug absorption as a set of dimensionless numbers viz

BCS defines 3 numbers (no units)

An ~ absorption number Do ~ dose number Dn ~ dissolution number

ABS

GI

GI

eff

TT

TR

PAn

Effective permeability

Radius of GI

Residence time in GI

Time required forcomplete absorption

Absorption NumberA function of GI Permeability to Drug Substance

S

Water

CV

DDo

Highest Dose Unit

250 mL

Solubility

Dose NumberA function of solubility of drug substance

Solubility mgmL

DISS

GI

GI

S

TT

TC

rD

Dn2

3Diffusivity5x10-6 cm2s

Density12 mgcm3

Particle Radiusm

Residence time in GI 180 min

Time required forcomplete dissolution

Dissolution NumberA function of drug release from formulation

IVIVC expectations for immediate release products based on BCS

Class Solubility Permeability Absorption rate control

IVIVC expectations for Immediate release product

I High High Gastric emptying

IVIVC expected if dissolution rate is slower than gastric emptying rate otherwise limited or no correlations

II Low High Dissolution IVIVC expected if in vitro dissolution rate is similar to in vivo dissolution rate unless dose is very high

III High Low Permeability Absorption (permeability) is rate determining and limited or no IVIVC with dissolution

IV Low Low Case by case

Limited or no IVIVC is expected

High Solubility Low Solubility H

igh

Pe

rmea

bil

ity

Class 1 Abacavir Acetaminophen Acyclovirb AmilorideSI

Amitryptyline SI Antipyrine Atropine Buspironec Caffeine Captopril ChloroquineSI

Chlorpheniramine Cyclophosphamide Desipramine Diazepam Diltiazem SI Diphenhydramine Disopyramide Doxepin Doxycycline Enalapril Ephedrine Ergonovine Ethambutol Ethinyl Estradiol FluoxetineI

Glucose

ImipramineI Ketorolac Ketoprofen Labetolol LevodopaS Levofloxacin S LidocaineI Lomefloxacin Meperidine Metoprolol Metronidazole MidazolamSI Minocycline Misoprostol Nifedipine S Phenobarbital Phenylalanine Prednisolone PrimaquineS Promazine Propranolol I QuinidineSI Rosiglitazone Salicylic acid Theophylline Valproic acid Verapamil I Zidovudine

Class 2 Amiodarone I AtorvastatinS I AzithromycinS I

Carbamazepine SI Carvedilol Chlorpromazine I CisaprideS

Ciprofloxacin S Cyclosporine S I Danazol Dapsone Diclofenac Diflunisal Digoxin S Erythromycin SI Flurbiprofen Glipizide GlyburideSI Griseofulvin Ibuprofen Indinavir S

Indomethacin

Itraconazole SI Ketoconazole I LansoprazoleI Lovastatin SI Mebendazole Naproxen Nelfinavir SI Ofloxacin Oxaprozin Phenazopyridine PhenytoinS Piroxicam Raloxifene S Ritonavir SI Saquinavir SI Sirolimus S Spironolactone I Tacrolimus SI TalinololS

Tamoxifen I Terfenadine I Warfarin

High Solubility Low Solubility Lo

w P

erm

eabi

lity

Class 3 Acyclovir Amiloride SI Amoxicillin SI Atenolol Atropine Bisphosphonates Bidisomide Captopril Cefazolin Cetirizine Cimetidine S Ciprofloxacin S Cloxacillin Dicloxacillin S Erythromycin SI

Famotidine

Fexofenadine S Folinic acid Furosemide Ganciclovir Hydrochlorothiazide Lisinopril Metformin Methotrexate Nadolol Pravastatin S Penicillins Ranitidine S Tetracycline Trimethoprim S Valsartan Zalcitabine

Class 4 Amphotericin B Chlorthalidone Chlorothiazide Colistin Ciprofloxacin S Furosemide Hydrochlorothiazide Mebendazole Methotrexate Neomycin

Applications of BCS in oral drug delivery technology

Achieve a target release profile associated with a particular pharmacokinetic andor pharmacodynamic profile

Formulation approaches include both control of release rate and certain physicochemical properties of drugs like pH-solubility profile of drug

Class I - High Permeability High Solubility

Micronisation

Addition of surfactants

Formulation as emulsions and microemulsions systems

Use of complexing agents like cyclodextrins

Class II - High Permeability

Low Solubility

Require the technologies that address to fundamental limitations of absolute or regional permeability

Peptides and proteins constitute the part of class III and the technologies handling such materials are on rise now days

Class III - Low Permeability High Solubility

Class IV - Low Permeability Low Solubility

Major challenge for development of drug delivery system and the route of choice for administering such drugs is parenteral (solubility enhancers)

Fortunately extreme examples are the exception rather than the rule and are rarely developed and reach the market

Biowaiver A biowaiver is an exemption from

conducting human bioequivalence studies when the active ingredient(s) meet certain solubility and permeability criteria in vitro and when the dissolution profile of the dosage form meets the requirements for an immediate release dosage form

Waiver of In Vivo Bioequivalence Study based on

Pharmaceutical Dosage Form (Solutions)

Biopharmaceutics Classification System

Dose (Highest Strength should be tested)

BCS BIOWAIVER

Biowaiver for

Rapid and similar dissolution High solubility ampHigh permeability Wide therapeutic window Excipients used in dosage form used

previously in approved IR solid dosage forms

REQUEST FOR BIOWAIVERS

Data Supporting -

Rapid and Similar Dissolution

High Permeability

High Solubility

Limitations of BCS as a Predictor of Drug

DispositionΩ Permeability (90 absorption) is difficult to

determine and difficult to convince the regulatory agency

Ω There is little predictability for BCS classification drugs beyond Class 1 primarily due to the difficulty of determining and proving 90 absorption many drugs are misclassified (eg HIV protease inhibitors

as Class 4 compounds))

Conclusion BCS aims to provide a regulatory tool for

replacing certain BE studies by accurate in-vitro dissolution tests

This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in

drug molecules with a sufficiently high permeability solubility and dissolution

rate and that will automatically increase the importance of the BCS as

a regulatory tool over time

References Draft guidance for industry waiver of in vivo

bioavailability and bioequivalence studies for immediate release solid oral dosage forms containing certain active moieties active ingredients based on a biopharmaceutic classification system february 1999 CDERFDA

Amidon GL Lennernas H Shah VP Crison JRA A theoretical basis for a biopharmaceutic drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharm Res 12 413-420 (1995)

Guidance for industry immediate release solid oral dosage forms scale up and post approval changes november 1995 CDERFDA

Medicamento generico from website httpwwwAnvisaGo

Devane J Oral drug delivery technology addressing the solubility permeability paradigm pharm Technol 68-74 november 1998

Amidon G LLennernaumls H Shah V P And crisonj R A theoretical basis for a biopharmaceutics drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharmaceutical research 12 413-420 (1995)

Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA CDER 1997 1048603httpwwwfdagovcderguidance1713bp1pdf

Guidance for Industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System FDA CDER August 2000 httpwwwfdagovcderguidance3618fnlhtm

Thank you

• BIOPHARMACEUTICS CLASSIFICATION SYSTEM
• Contents
• Introduction
• Slide 4
• Slide 5
• Biopharmaceutics Classification System
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• DISSOLUTION DETERMINATION
• CLASS BOUNDARIES
• BCS Class Boundaries Objectives
• Slide 15
• BCS -Implications for drug development
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Applications of BCS in oral drug delivery technology
• Class II - High Permeability Low Solubility
• Slide 27
• Slide 28
• Biowaiver
• Waiver of In Vivo Bioequivalence Study based on
• BCS BIOWAIVER
• REQUEST FOR BIOWAIVERS
• Limitations of BCS as a Predictor of Drug Disposition
• Conclusion
• References
• Slide 36
• Slide 37

The Biopharmaceutics Classification System (BCS)(as defined by the FDA after Amidon)

SIMILAR IN VIVO DISSOLUTION

SIMILAR IN VIVO ABSORPTION

SIMILAR SYSTEMIC AVAILABILITY

Dissolution of drug in vivo

Drug Concentration in the Membrane Domain

Intestinal Absorption

determines

proportional

Basis of BCS

(37plusmn100C in aqueous medium with pH range of 1-75)

A sufficient number of pH conditions ionization characteristics of the test drug substance

A minimum of three replicate determinations of solubility in each pH condition

Standard buffer solutions described in pharmacopoeias Methods other than shake flask method (with

Justification) e g acid or base titration methods

SOLUBILITY DETERMINATION

clubsNot just based on lipophilicity (encompass in vivo effects of efflux and uptake transporters)

A Human studies Mass balance studies Absolute bioavailability studies Intestinal perfusion methods

BIn vivo or in situ intestinal perfusion in a suitable animal model

CIn vitro permeability methods using excised intestinal tissues

D In vitro permeation studies across a monolayer of cultured epithelial cellseg Caco-2 cells or TC-7 cells

Determination of permeability

DISSOLUTION DETERMINATION

USP apparatus I (basket) at 100 rpm or USP apparatus II (paddle) at 50 rpm

Dissolution media (900 ml) 01 N HCl or simulated gastric fluid pH 45 buffer and pH 68 buffer or simulated intestinal fluid

Compare dissolution profiles of test and reference products using a similarity factor (f2)

0

CLASS BOUNDARIES

HIGHLY SOLUBLE the highest dose strength is soluble in lt 250 ml water over a pH range of 1 to 75

The volume estimate-a glassful (8 ounce)

HIGHLY PERMEABLE when the extent of absorption in humans is determined to be gt 90 of an administered dose

RAPIDLY DISSOLVING when gt 85 of the labeled amount of drug substance dissolves within 30 minutes using USP apparatus I or II in a volume of lt 900 ml buffer solutions

BCS Class Boundaries Objectives

Dissolution(Product)

Solubility (Drug)

Permeability

(Drug)

Rapid dissolution - ensure that in vivo dissolution is not likely to be theldquorate determiningrdquo step

High solubility- ensure that solubilityis not likely to limit dissolution and therefore absorption

High permeability - ensure that drugis completely absorbed during the limitedtransit time through the small intestine

BCS -Implications for drug developmentЖApplication in early drug development and then in

the management of product change through its life cycle

ЖAids fundamental understanding of the biopharmaceutical and physical properties of the drug

ЖAids discriminatory dissolution method development

ЖCan help guide the development of in-vitroin-vivo correlations

ЖCan be used to obtain a biowaiver

ЖDevelopment of poorly soluble drugs

This classification is associated with drug dissolution and absorption model which identifies the key parameters controlling drug absorption as a set of dimensionless numbers viz

BCS defines 3 numbers (no units)

An ~ absorption number Do ~ dose number Dn ~ dissolution number

ABS

GI

GI

eff

TT

TR

PAn

Effective permeability

Radius of GI

Residence time in GI

Time required forcomplete absorption

Absorption NumberA function of GI Permeability to Drug Substance

S

Water

CV

DDo

Highest Dose Unit

250 mL

Solubility

Dose NumberA function of solubility of drug substance

Solubility mgmL

DISS

GI

GI

S

TT

TC

rD

Dn2

3Diffusivity5x10-6 cm2s

Density12 mgcm3

Particle Radiusm

Residence time in GI 180 min

Time required forcomplete dissolution

Dissolution NumberA function of drug release from formulation

IVIVC expectations for immediate release products based on BCS

Class Solubility Permeability Absorption rate control

IVIVC expectations for Immediate release product

I High High Gastric emptying

IVIVC expected if dissolution rate is slower than gastric emptying rate otherwise limited or no correlations

II Low High Dissolution IVIVC expected if in vitro dissolution rate is similar to in vivo dissolution rate unless dose is very high

III High Low Permeability Absorption (permeability) is rate determining and limited or no IVIVC with dissolution

IV Low Low Case by case

Limited or no IVIVC is expected

High Solubility Low Solubility H

igh

Pe

rmea

bil

ity

Class 1 Abacavir Acetaminophen Acyclovirb AmilorideSI

Amitryptyline SI Antipyrine Atropine Buspironec Caffeine Captopril ChloroquineSI

Chlorpheniramine Cyclophosphamide Desipramine Diazepam Diltiazem SI Diphenhydramine Disopyramide Doxepin Doxycycline Enalapril Ephedrine Ergonovine Ethambutol Ethinyl Estradiol FluoxetineI

Glucose

ImipramineI Ketorolac Ketoprofen Labetolol LevodopaS Levofloxacin S LidocaineI Lomefloxacin Meperidine Metoprolol Metronidazole MidazolamSI Minocycline Misoprostol Nifedipine S Phenobarbital Phenylalanine Prednisolone PrimaquineS Promazine Propranolol I QuinidineSI Rosiglitazone Salicylic acid Theophylline Valproic acid Verapamil I Zidovudine

Class 2 Amiodarone I AtorvastatinS I AzithromycinS I

Carbamazepine SI Carvedilol Chlorpromazine I CisaprideS

Ciprofloxacin S Cyclosporine S I Danazol Dapsone Diclofenac Diflunisal Digoxin S Erythromycin SI Flurbiprofen Glipizide GlyburideSI Griseofulvin Ibuprofen Indinavir S

Indomethacin

Itraconazole SI Ketoconazole I LansoprazoleI Lovastatin SI Mebendazole Naproxen Nelfinavir SI Ofloxacin Oxaprozin Phenazopyridine PhenytoinS Piroxicam Raloxifene S Ritonavir SI Saquinavir SI Sirolimus S Spironolactone I Tacrolimus SI TalinololS

Tamoxifen I Terfenadine I Warfarin

High Solubility Low Solubility Lo

w P

erm

eabi

lity

Class 3 Acyclovir Amiloride SI Amoxicillin SI Atenolol Atropine Bisphosphonates Bidisomide Captopril Cefazolin Cetirizine Cimetidine S Ciprofloxacin S Cloxacillin Dicloxacillin S Erythromycin SI

Famotidine

Fexofenadine S Folinic acid Furosemide Ganciclovir Hydrochlorothiazide Lisinopril Metformin Methotrexate Nadolol Pravastatin S Penicillins Ranitidine S Tetracycline Trimethoprim S Valsartan Zalcitabine

Class 4 Amphotericin B Chlorthalidone Chlorothiazide Colistin Ciprofloxacin S Furosemide Hydrochlorothiazide Mebendazole Methotrexate Neomycin

Applications of BCS in oral drug delivery technology

Achieve a target release profile associated with a particular pharmacokinetic andor pharmacodynamic profile

Formulation approaches include both control of release rate and certain physicochemical properties of drugs like pH-solubility profile of drug

Class I - High Permeability High Solubility

Micronisation

Addition of surfactants

Formulation as emulsions and microemulsions systems

Use of complexing agents like cyclodextrins

Class II - High Permeability

Low Solubility

Require the technologies that address to fundamental limitations of absolute or regional permeability

Peptides and proteins constitute the part of class III and the technologies handling such materials are on rise now days

Class III - Low Permeability High Solubility

Class IV - Low Permeability Low Solubility

Major challenge for development of drug delivery system and the route of choice for administering such drugs is parenteral (solubility enhancers)

Fortunately extreme examples are the exception rather than the rule and are rarely developed and reach the market

Biowaiver A biowaiver is an exemption from

conducting human bioequivalence studies when the active ingredient(s) meet certain solubility and permeability criteria in vitro and when the dissolution profile of the dosage form meets the requirements for an immediate release dosage form

Waiver of In Vivo Bioequivalence Study based on

Pharmaceutical Dosage Form (Solutions)

Biopharmaceutics Classification System

Dose (Highest Strength should be tested)

BCS BIOWAIVER

Biowaiver for

Rapid and similar dissolution High solubility ampHigh permeability Wide therapeutic window Excipients used in dosage form used

previously in approved IR solid dosage forms

REQUEST FOR BIOWAIVERS

Data Supporting -

Rapid and Similar Dissolution

High Permeability

High Solubility

Limitations of BCS as a Predictor of Drug

DispositionΩ Permeability (90 absorption) is difficult to

determine and difficult to convince the regulatory agency

Ω There is little predictability for BCS classification drugs beyond Class 1 primarily due to the difficulty of determining and proving 90 absorption many drugs are misclassified (eg HIV protease inhibitors

as Class 4 compounds))

Conclusion BCS aims to provide a regulatory tool for

replacing certain BE studies by accurate in-vitro dissolution tests

This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in

drug molecules with a sufficiently high permeability solubility and dissolution

rate and that will automatically increase the importance of the BCS as

a regulatory tool over time

References Draft guidance for industry waiver of in vivo

bioavailability and bioequivalence studies for immediate release solid oral dosage forms containing certain active moieties active ingredients based on a biopharmaceutic classification system february 1999 CDERFDA

Amidon GL Lennernas H Shah VP Crison JRA A theoretical basis for a biopharmaceutic drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharm Res 12 413-420 (1995)

Guidance for industry immediate release solid oral dosage forms scale up and post approval changes november 1995 CDERFDA

Medicamento generico from website httpwwwAnvisaGo

Devane J Oral drug delivery technology addressing the solubility permeability paradigm pharm Technol 68-74 november 1998

Amidon G LLennernaumls H Shah V P And crisonj R A theoretical basis for a biopharmaceutics drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharmaceutical research 12 413-420 (1995)

Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA CDER 1997 1048603httpwwwfdagovcderguidance1713bp1pdf

Guidance for Industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System FDA CDER August 2000 httpwwwfdagovcderguidance3618fnlhtm

Thank you

• BIOPHARMACEUTICS CLASSIFICATION SYSTEM
• Contents
• Introduction
• Slide 4
• Slide 5
• Biopharmaceutics Classification System
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• DISSOLUTION DETERMINATION
• CLASS BOUNDARIES
• BCS Class Boundaries Objectives
• Slide 15
• BCS -Implications for drug development
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Applications of BCS in oral drug delivery technology
• Class II - High Permeability Low Solubility
• Slide 27
• Slide 28
• Biowaiver
• Waiver of In Vivo Bioequivalence Study based on
• BCS BIOWAIVER
• REQUEST FOR BIOWAIVERS
• Limitations of BCS as a Predictor of Drug Disposition
• Conclusion
• References
• Slide 36
• Slide 37

SIMILAR IN VIVO DISSOLUTION

SIMILAR IN VIVO ABSORPTION

SIMILAR SYSTEMIC AVAILABILITY

Dissolution of drug in vivo

Drug Concentration in the Membrane Domain

Intestinal Absorption

determines

proportional

Basis of BCS

(37plusmn100C in aqueous medium with pH range of 1-75)

A sufficient number of pH conditions ionization characteristics of the test drug substance

A minimum of three replicate determinations of solubility in each pH condition

Standard buffer solutions described in pharmacopoeias Methods other than shake flask method (with

Justification) e g acid or base titration methods

SOLUBILITY DETERMINATION

clubsNot just based on lipophilicity (encompass in vivo effects of efflux and uptake transporters)

A Human studies Mass balance studies Absolute bioavailability studies Intestinal perfusion methods

BIn vivo or in situ intestinal perfusion in a suitable animal model

CIn vitro permeability methods using excised intestinal tissues

D In vitro permeation studies across a monolayer of cultured epithelial cellseg Caco-2 cells or TC-7 cells

Determination of permeability

DISSOLUTION DETERMINATION

USP apparatus I (basket) at 100 rpm or USP apparatus II (paddle) at 50 rpm

Dissolution media (900 ml) 01 N HCl or simulated gastric fluid pH 45 buffer and pH 68 buffer or simulated intestinal fluid

Compare dissolution profiles of test and reference products using a similarity factor (f2)

0

CLASS BOUNDARIES

HIGHLY SOLUBLE the highest dose strength is soluble in lt 250 ml water over a pH range of 1 to 75

The volume estimate-a glassful (8 ounce)

HIGHLY PERMEABLE when the extent of absorption in humans is determined to be gt 90 of an administered dose

RAPIDLY DISSOLVING when gt 85 of the labeled amount of drug substance dissolves within 30 minutes using USP apparatus I or II in a volume of lt 900 ml buffer solutions

BCS Class Boundaries Objectives

Dissolution(Product)

Solubility (Drug)

Permeability

(Drug)

Rapid dissolution - ensure that in vivo dissolution is not likely to be theldquorate determiningrdquo step

High solubility- ensure that solubilityis not likely to limit dissolution and therefore absorption

High permeability - ensure that drugis completely absorbed during the limitedtransit time through the small intestine

BCS -Implications for drug developmentЖApplication in early drug development and then in

the management of product change through its life cycle

ЖAids fundamental understanding of the biopharmaceutical and physical properties of the drug

ЖAids discriminatory dissolution method development

ЖCan help guide the development of in-vitroin-vivo correlations

ЖCan be used to obtain a biowaiver

ЖDevelopment of poorly soluble drugs

This classification is associated with drug dissolution and absorption model which identifies the key parameters controlling drug absorption as a set of dimensionless numbers viz

BCS defines 3 numbers (no units)

An ~ absorption number Do ~ dose number Dn ~ dissolution number

ABS

GI

GI

eff

TT

TR

PAn

Effective permeability

Radius of GI

Residence time in GI

Time required forcomplete absorption

Absorption NumberA function of GI Permeability to Drug Substance

S

Water

CV

DDo

Highest Dose Unit

250 mL

Solubility

Dose NumberA function of solubility of drug substance

Solubility mgmL

DISS

GI

GI

S

TT

TC

rD

Dn2

3Diffusivity5x10-6 cm2s

Density12 mgcm3

Particle Radiusm

Residence time in GI 180 min

Time required forcomplete dissolution

Dissolution NumberA function of drug release from formulation

IVIVC expectations for immediate release products based on BCS

Class Solubility Permeability Absorption rate control

IVIVC expectations for Immediate release product

I High High Gastric emptying

IVIVC expected if dissolution rate is slower than gastric emptying rate otherwise limited or no correlations

II Low High Dissolution IVIVC expected if in vitro dissolution rate is similar to in vivo dissolution rate unless dose is very high

III High Low Permeability Absorption (permeability) is rate determining and limited or no IVIVC with dissolution

IV Low Low Case by case

Limited or no IVIVC is expected

High Solubility Low Solubility H

igh

Pe

rmea

bil

ity

Class 1 Abacavir Acetaminophen Acyclovirb AmilorideSI

Amitryptyline SI Antipyrine Atropine Buspironec Caffeine Captopril ChloroquineSI

Chlorpheniramine Cyclophosphamide Desipramine Diazepam Diltiazem SI Diphenhydramine Disopyramide Doxepin Doxycycline Enalapril Ephedrine Ergonovine Ethambutol Ethinyl Estradiol FluoxetineI

Glucose

ImipramineI Ketorolac Ketoprofen Labetolol LevodopaS Levofloxacin S LidocaineI Lomefloxacin Meperidine Metoprolol Metronidazole MidazolamSI Minocycline Misoprostol Nifedipine S Phenobarbital Phenylalanine Prednisolone PrimaquineS Promazine Propranolol I QuinidineSI Rosiglitazone Salicylic acid Theophylline Valproic acid Verapamil I Zidovudine

Class 2 Amiodarone I AtorvastatinS I AzithromycinS I

Carbamazepine SI Carvedilol Chlorpromazine I CisaprideS

Ciprofloxacin S Cyclosporine S I Danazol Dapsone Diclofenac Diflunisal Digoxin S Erythromycin SI Flurbiprofen Glipizide GlyburideSI Griseofulvin Ibuprofen Indinavir S

Indomethacin

Itraconazole SI Ketoconazole I LansoprazoleI Lovastatin SI Mebendazole Naproxen Nelfinavir SI Ofloxacin Oxaprozin Phenazopyridine PhenytoinS Piroxicam Raloxifene S Ritonavir SI Saquinavir SI Sirolimus S Spironolactone I Tacrolimus SI TalinololS

Tamoxifen I Terfenadine I Warfarin

High Solubility Low Solubility Lo

w P

erm

eabi

lity

Class 3 Acyclovir Amiloride SI Amoxicillin SI Atenolol Atropine Bisphosphonates Bidisomide Captopril Cefazolin Cetirizine Cimetidine S Ciprofloxacin S Cloxacillin Dicloxacillin S Erythromycin SI

Famotidine

Fexofenadine S Folinic acid Furosemide Ganciclovir Hydrochlorothiazide Lisinopril Metformin Methotrexate Nadolol Pravastatin S Penicillins Ranitidine S Tetracycline Trimethoprim S Valsartan Zalcitabine

Class 4 Amphotericin B Chlorthalidone Chlorothiazide Colistin Ciprofloxacin S Furosemide Hydrochlorothiazide Mebendazole Methotrexate Neomycin

Applications of BCS in oral drug delivery technology

Achieve a target release profile associated with a particular pharmacokinetic andor pharmacodynamic profile

Formulation approaches include both control of release rate and certain physicochemical properties of drugs like pH-solubility profile of drug

Class I - High Permeability High Solubility

Micronisation

Addition of surfactants

Formulation as emulsions and microemulsions systems

Use of complexing agents like cyclodextrins

Class II - High Permeability

Low Solubility

Require the technologies that address to fundamental limitations of absolute or regional permeability

Peptides and proteins constitute the part of class III and the technologies handling such materials are on rise now days

Class III - Low Permeability High Solubility

Class IV - Low Permeability Low Solubility

Major challenge for development of drug delivery system and the route of choice for administering such drugs is parenteral (solubility enhancers)

Fortunately extreme examples are the exception rather than the rule and are rarely developed and reach the market

Biowaiver A biowaiver is an exemption from

conducting human bioequivalence studies when the active ingredient(s) meet certain solubility and permeability criteria in vitro and when the dissolution profile of the dosage form meets the requirements for an immediate release dosage form

Waiver of In Vivo Bioequivalence Study based on

Pharmaceutical Dosage Form (Solutions)

Biopharmaceutics Classification System

Dose (Highest Strength should be tested)

BCS BIOWAIVER

Biowaiver for

Rapid and similar dissolution High solubility ampHigh permeability Wide therapeutic window Excipients used in dosage form used

previously in approved IR solid dosage forms

REQUEST FOR BIOWAIVERS

Data Supporting -

Rapid and Similar Dissolution

High Permeability

High Solubility

Limitations of BCS as a Predictor of Drug

DispositionΩ Permeability (90 absorption) is difficult to

determine and difficult to convince the regulatory agency

Ω There is little predictability for BCS classification drugs beyond Class 1 primarily due to the difficulty of determining and proving 90 absorption many drugs are misclassified (eg HIV protease inhibitors

as Class 4 compounds))

Conclusion BCS aims to provide a regulatory tool for

replacing certain BE studies by accurate in-vitro dissolution tests

This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in

drug molecules with a sufficiently high permeability solubility and dissolution

rate and that will automatically increase the importance of the BCS as

a regulatory tool over time

References Draft guidance for industry waiver of in vivo

bioavailability and bioequivalence studies for immediate release solid oral dosage forms containing certain active moieties active ingredients based on a biopharmaceutic classification system february 1999 CDERFDA

Amidon GL Lennernas H Shah VP Crison JRA A theoretical basis for a biopharmaceutic drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharm Res 12 413-420 (1995)

Guidance for industry immediate release solid oral dosage forms scale up and post approval changes november 1995 CDERFDA

Medicamento generico from website httpwwwAnvisaGo

Devane J Oral drug delivery technology addressing the solubility permeability paradigm pharm Technol 68-74 november 1998

Amidon G LLennernaumls H Shah V P And crisonj R A theoretical basis for a biopharmaceutics drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharmaceutical research 12 413-420 (1995)

Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA CDER 1997 1048603httpwwwfdagovcderguidance1713bp1pdf

Guidance for Industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System FDA CDER August 2000 httpwwwfdagovcderguidance3618fnlhtm

Thank you

• BIOPHARMACEUTICS CLASSIFICATION SYSTEM
• Contents
• Introduction
• Slide 4
• Slide 5
• Biopharmaceutics Classification System
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• DISSOLUTION DETERMINATION
• CLASS BOUNDARIES
• BCS Class Boundaries Objectives
• Slide 15
• BCS -Implications for drug development
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Applications of BCS in oral drug delivery technology
• Class II - High Permeability Low Solubility
• Slide 27
• Slide 28
• Biowaiver
• Waiver of In Vivo Bioequivalence Study based on
• BCS BIOWAIVER
• REQUEST FOR BIOWAIVERS
• Limitations of BCS as a Predictor of Drug Disposition
• Conclusion
• References
• Slide 36
• Slide 37

(37plusmn100C in aqueous medium with pH range of 1-75)

A sufficient number of pH conditions ionization characteristics of the test drug substance

A minimum of three replicate determinations of solubility in each pH condition

Standard buffer solutions described in pharmacopoeias Methods other than shake flask method (with

Justification) e g acid or base titration methods

SOLUBILITY DETERMINATION

clubsNot just based on lipophilicity (encompass in vivo effects of efflux and uptake transporters)

A Human studies Mass balance studies Absolute bioavailability studies Intestinal perfusion methods

BIn vivo or in situ intestinal perfusion in a suitable animal model

CIn vitro permeability methods using excised intestinal tissues

D In vitro permeation studies across a monolayer of cultured epithelial cellseg Caco-2 cells or TC-7 cells

Determination of permeability

DISSOLUTION DETERMINATION

USP apparatus I (basket) at 100 rpm or USP apparatus II (paddle) at 50 rpm

Dissolution media (900 ml) 01 N HCl or simulated gastric fluid pH 45 buffer and pH 68 buffer or simulated intestinal fluid

Compare dissolution profiles of test and reference products using a similarity factor (f2)

0

CLASS BOUNDARIES

HIGHLY SOLUBLE the highest dose strength is soluble in lt 250 ml water over a pH range of 1 to 75

The volume estimate-a glassful (8 ounce)

HIGHLY PERMEABLE when the extent of absorption in humans is determined to be gt 90 of an administered dose

RAPIDLY DISSOLVING when gt 85 of the labeled amount of drug substance dissolves within 30 minutes using USP apparatus I or II in a volume of lt 900 ml buffer solutions

BCS Class Boundaries Objectives

Dissolution(Product)

Solubility (Drug)

Permeability

(Drug)

Rapid dissolution - ensure that in vivo dissolution is not likely to be theldquorate determiningrdquo step

High solubility- ensure that solubilityis not likely to limit dissolution and therefore absorption

High permeability - ensure that drugis completely absorbed during the limitedtransit time through the small intestine

BCS -Implications for drug developmentЖApplication in early drug development and then in

the management of product change through its life cycle

ЖAids fundamental understanding of the biopharmaceutical and physical properties of the drug

ЖAids discriminatory dissolution method development

ЖCan help guide the development of in-vitroin-vivo correlations

ЖCan be used to obtain a biowaiver

ЖDevelopment of poorly soluble drugs

This classification is associated with drug dissolution and absorption model which identifies the key parameters controlling drug absorption as a set of dimensionless numbers viz

BCS defines 3 numbers (no units)

An ~ absorption number Do ~ dose number Dn ~ dissolution number

ABS

GI

GI

eff

TT

TR

PAn

Effective permeability

Radius of GI

Residence time in GI

Time required forcomplete absorption

Absorption NumberA function of GI Permeability to Drug Substance

S

Water

CV

DDo

Highest Dose Unit

250 mL

Solubility

Dose NumberA function of solubility of drug substance

Solubility mgmL

DISS

GI

GI

S

TT

TC

rD

Dn2

3Diffusivity5x10-6 cm2s

Density12 mgcm3

Particle Radiusm

Residence time in GI 180 min

Time required forcomplete dissolution

Dissolution NumberA function of drug release from formulation

IVIVC expectations for immediate release products based on BCS

Class Solubility Permeability Absorption rate control

IVIVC expectations for Immediate release product

I High High Gastric emptying

IVIVC expected if dissolution rate is slower than gastric emptying rate otherwise limited or no correlations

II Low High Dissolution IVIVC expected if in vitro dissolution rate is similar to in vivo dissolution rate unless dose is very high

III High Low Permeability Absorption (permeability) is rate determining and limited or no IVIVC with dissolution

IV Low Low Case by case

Limited or no IVIVC is expected

High Solubility Low Solubility H

igh

Pe

rmea

bil

ity

Class 1 Abacavir Acetaminophen Acyclovirb AmilorideSI

Amitryptyline SI Antipyrine Atropine Buspironec Caffeine Captopril ChloroquineSI

Chlorpheniramine Cyclophosphamide Desipramine Diazepam Diltiazem SI Diphenhydramine Disopyramide Doxepin Doxycycline Enalapril Ephedrine Ergonovine Ethambutol Ethinyl Estradiol FluoxetineI

Glucose

ImipramineI Ketorolac Ketoprofen Labetolol LevodopaS Levofloxacin S LidocaineI Lomefloxacin Meperidine Metoprolol Metronidazole MidazolamSI Minocycline Misoprostol Nifedipine S Phenobarbital Phenylalanine Prednisolone PrimaquineS Promazine Propranolol I QuinidineSI Rosiglitazone Salicylic acid Theophylline Valproic acid Verapamil I Zidovudine

Class 2 Amiodarone I AtorvastatinS I AzithromycinS I

Carbamazepine SI Carvedilol Chlorpromazine I CisaprideS

Ciprofloxacin S Cyclosporine S I Danazol Dapsone Diclofenac Diflunisal Digoxin S Erythromycin SI Flurbiprofen Glipizide GlyburideSI Griseofulvin Ibuprofen Indinavir S

Indomethacin

Itraconazole SI Ketoconazole I LansoprazoleI Lovastatin SI Mebendazole Naproxen Nelfinavir SI Ofloxacin Oxaprozin Phenazopyridine PhenytoinS Piroxicam Raloxifene S Ritonavir SI Saquinavir SI Sirolimus S Spironolactone I Tacrolimus SI TalinololS

Tamoxifen I Terfenadine I Warfarin

High Solubility Low Solubility Lo

w P

erm

eabi

lity

Class 3 Acyclovir Amiloride SI Amoxicillin SI Atenolol Atropine Bisphosphonates Bidisomide Captopril Cefazolin Cetirizine Cimetidine S Ciprofloxacin S Cloxacillin Dicloxacillin S Erythromycin SI

Famotidine

Fexofenadine S Folinic acid Furosemide Ganciclovir Hydrochlorothiazide Lisinopril Metformin Methotrexate Nadolol Pravastatin S Penicillins Ranitidine S Tetracycline Trimethoprim S Valsartan Zalcitabine

Class 4 Amphotericin B Chlorthalidone Chlorothiazide Colistin Ciprofloxacin S Furosemide Hydrochlorothiazide Mebendazole Methotrexate Neomycin

Applications of BCS in oral drug delivery technology

Achieve a target release profile associated with a particular pharmacokinetic andor pharmacodynamic profile

Formulation approaches include both control of release rate and certain physicochemical properties of drugs like pH-solubility profile of drug

Class I - High Permeability High Solubility

Micronisation

Addition of surfactants

Formulation as emulsions and microemulsions systems

Use of complexing agents like cyclodextrins

Class II - High Permeability

Low Solubility

Require the technologies that address to fundamental limitations of absolute or regional permeability

Peptides and proteins constitute the part of class III and the technologies handling such materials are on rise now days

Class III - Low Permeability High Solubility

Class IV - Low Permeability Low Solubility

Major challenge for development of drug delivery system and the route of choice for administering such drugs is parenteral (solubility enhancers)

Fortunately extreme examples are the exception rather than the rule and are rarely developed and reach the market

Biowaiver A biowaiver is an exemption from

conducting human bioequivalence studies when the active ingredient(s) meet certain solubility and permeability criteria in vitro and when the dissolution profile of the dosage form meets the requirements for an immediate release dosage form

Waiver of In Vivo Bioequivalence Study based on

Pharmaceutical Dosage Form (Solutions)

Biopharmaceutics Classification System

Dose (Highest Strength should be tested)

BCS BIOWAIVER

Biowaiver for

Rapid and similar dissolution High solubility ampHigh permeability Wide therapeutic window Excipients used in dosage form used

previously in approved IR solid dosage forms

REQUEST FOR BIOWAIVERS

Data Supporting -

Rapid and Similar Dissolution

High Permeability

High Solubility

Limitations of BCS as a Predictor of Drug

DispositionΩ Permeability (90 absorption) is difficult to

determine and difficult to convince the regulatory agency

Ω There is little predictability for BCS classification drugs beyond Class 1 primarily due to the difficulty of determining and proving 90 absorption many drugs are misclassified (eg HIV protease inhibitors

as Class 4 compounds))

Conclusion BCS aims to provide a regulatory tool for

replacing certain BE studies by accurate in-vitro dissolution tests

This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in

drug molecules with a sufficiently high permeability solubility and dissolution

rate and that will automatically increase the importance of the BCS as

a regulatory tool over time

References Draft guidance for industry waiver of in vivo

bioavailability and bioequivalence studies for immediate release solid oral dosage forms containing certain active moieties active ingredients based on a biopharmaceutic classification system february 1999 CDERFDA

Amidon GL Lennernas H Shah VP Crison JRA A theoretical basis for a biopharmaceutic drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharm Res 12 413-420 (1995)

Guidance for industry immediate release solid oral dosage forms scale up and post approval changes november 1995 CDERFDA

Medicamento generico from website httpwwwAnvisaGo

Devane J Oral drug delivery technology addressing the solubility permeability paradigm pharm Technol 68-74 november 1998

Amidon G LLennernaumls H Shah V P And crisonj R A theoretical basis for a biopharmaceutics drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharmaceutical research 12 413-420 (1995)

Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA CDER 1997 1048603httpwwwfdagovcderguidance1713bp1pdf

Guidance for Industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System FDA CDER August 2000 httpwwwfdagovcderguidance3618fnlhtm

Thank you

• BIOPHARMACEUTICS CLASSIFICATION SYSTEM
• Contents
• Introduction
• Slide 4
• Slide 5
• Biopharmaceutics Classification System
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• DISSOLUTION DETERMINATION
• CLASS BOUNDARIES
• BCS Class Boundaries Objectives
• Slide 15
• BCS -Implications for drug development
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Applications of BCS in oral drug delivery technology
• Class II - High Permeability Low Solubility
• Slide 27
• Slide 28
• Biowaiver
• Waiver of In Vivo Bioequivalence Study based on
• BCS BIOWAIVER
• REQUEST FOR BIOWAIVERS
• Limitations of BCS as a Predictor of Drug Disposition
• Conclusion
• References
• Slide 36
• Slide 37

clubsNot just based on lipophilicity (encompass in vivo effects of efflux and uptake transporters)

A Human studies Mass balance studies Absolute bioavailability studies Intestinal perfusion methods

BIn vivo or in situ intestinal perfusion in a suitable animal model

CIn vitro permeability methods using excised intestinal tissues

D In vitro permeation studies across a monolayer of cultured epithelial cellseg Caco-2 cells or TC-7 cells

Determination of permeability

DISSOLUTION DETERMINATION

USP apparatus I (basket) at 100 rpm or USP apparatus II (paddle) at 50 rpm

Dissolution media (900 ml) 01 N HCl or simulated gastric fluid pH 45 buffer and pH 68 buffer or simulated intestinal fluid

Compare dissolution profiles of test and reference products using a similarity factor (f2)

0

CLASS BOUNDARIES

HIGHLY SOLUBLE the highest dose strength is soluble in lt 250 ml water over a pH range of 1 to 75

The volume estimate-a glassful (8 ounce)

HIGHLY PERMEABLE when the extent of absorption in humans is determined to be gt 90 of an administered dose

RAPIDLY DISSOLVING when gt 85 of the labeled amount of drug substance dissolves within 30 minutes using USP apparatus I or II in a volume of lt 900 ml buffer solutions

BCS Class Boundaries Objectives

Dissolution(Product)

Solubility (Drug)

Permeability

(Drug)

Rapid dissolution - ensure that in vivo dissolution is not likely to be theldquorate determiningrdquo step

High solubility- ensure that solubilityis not likely to limit dissolution and therefore absorption

High permeability - ensure that drugis completely absorbed during the limitedtransit time through the small intestine

BCS -Implications for drug developmentЖApplication in early drug development and then in

the management of product change through its life cycle

ЖAids fundamental understanding of the biopharmaceutical and physical properties of the drug

ЖAids discriminatory dissolution method development

ЖCan help guide the development of in-vitroin-vivo correlations

ЖCan be used to obtain a biowaiver

ЖDevelopment of poorly soluble drugs

This classification is associated with drug dissolution and absorption model which identifies the key parameters controlling drug absorption as a set of dimensionless numbers viz

BCS defines 3 numbers (no units)

An ~ absorption number Do ~ dose number Dn ~ dissolution number

ABS

GI

GI

eff

TT

TR

PAn

Effective permeability

Radius of GI

Residence time in GI

Time required forcomplete absorption

Absorption NumberA function of GI Permeability to Drug Substance

S

Water

CV

DDo

Highest Dose Unit

250 mL

Solubility

Dose NumberA function of solubility of drug substance

Solubility mgmL

DISS

GI

GI

S

TT

TC

rD

Dn2

3Diffusivity5x10-6 cm2s

Density12 mgcm3

Particle Radiusm

Residence time in GI 180 min

Time required forcomplete dissolution

Dissolution NumberA function of drug release from formulation

IVIVC expectations for immediate release products based on BCS

Class Solubility Permeability Absorption rate control

IVIVC expectations for Immediate release product

I High High Gastric emptying

IVIVC expected if dissolution rate is slower than gastric emptying rate otherwise limited or no correlations

II Low High Dissolution IVIVC expected if in vitro dissolution rate is similar to in vivo dissolution rate unless dose is very high

III High Low Permeability Absorption (permeability) is rate determining and limited or no IVIVC with dissolution

IV Low Low Case by case

Limited or no IVIVC is expected

High Solubility Low Solubility H

igh

Pe

rmea

bil

ity

Class 1 Abacavir Acetaminophen Acyclovirb AmilorideSI

Amitryptyline SI Antipyrine Atropine Buspironec Caffeine Captopril ChloroquineSI

Chlorpheniramine Cyclophosphamide Desipramine Diazepam Diltiazem SI Diphenhydramine Disopyramide Doxepin Doxycycline Enalapril Ephedrine Ergonovine Ethambutol Ethinyl Estradiol FluoxetineI

Glucose

ImipramineI Ketorolac Ketoprofen Labetolol LevodopaS Levofloxacin S LidocaineI Lomefloxacin Meperidine Metoprolol Metronidazole MidazolamSI Minocycline Misoprostol Nifedipine S Phenobarbital Phenylalanine Prednisolone PrimaquineS Promazine Propranolol I QuinidineSI Rosiglitazone Salicylic acid Theophylline Valproic acid Verapamil I Zidovudine

Class 2 Amiodarone I AtorvastatinS I AzithromycinS I

Carbamazepine SI Carvedilol Chlorpromazine I CisaprideS

Ciprofloxacin S Cyclosporine S I Danazol Dapsone Diclofenac Diflunisal Digoxin S Erythromycin SI Flurbiprofen Glipizide GlyburideSI Griseofulvin Ibuprofen Indinavir S

Indomethacin

Itraconazole SI Ketoconazole I LansoprazoleI Lovastatin SI Mebendazole Naproxen Nelfinavir SI Ofloxacin Oxaprozin Phenazopyridine PhenytoinS Piroxicam Raloxifene S Ritonavir SI Saquinavir SI Sirolimus S Spironolactone I Tacrolimus SI TalinololS

Tamoxifen I Terfenadine I Warfarin

High Solubility Low Solubility Lo

w P

erm

eabi

lity

Class 3 Acyclovir Amiloride SI Amoxicillin SI Atenolol Atropine Bisphosphonates Bidisomide Captopril Cefazolin Cetirizine Cimetidine S Ciprofloxacin S Cloxacillin Dicloxacillin S Erythromycin SI

Famotidine

Fexofenadine S Folinic acid Furosemide Ganciclovir Hydrochlorothiazide Lisinopril Metformin Methotrexate Nadolol Pravastatin S Penicillins Ranitidine S Tetracycline Trimethoprim S Valsartan Zalcitabine

Class 4 Amphotericin B Chlorthalidone Chlorothiazide Colistin Ciprofloxacin S Furosemide Hydrochlorothiazide Mebendazole Methotrexate Neomycin

Applications of BCS in oral drug delivery technology

Achieve a target release profile associated with a particular pharmacokinetic andor pharmacodynamic profile

Formulation approaches include both control of release rate and certain physicochemical properties of drugs like pH-solubility profile of drug

Class I - High Permeability High Solubility

Micronisation

Addition of surfactants

Formulation as emulsions and microemulsions systems

Use of complexing agents like cyclodextrins

Class II - High Permeability

Low Solubility

Require the technologies that address to fundamental limitations of absolute or regional permeability

Peptides and proteins constitute the part of class III and the technologies handling such materials are on rise now days

Class III - Low Permeability High Solubility

Class IV - Low Permeability Low Solubility

Major challenge for development of drug delivery system and the route of choice for administering such drugs is parenteral (solubility enhancers)

Fortunately extreme examples are the exception rather than the rule and are rarely developed and reach the market

Biowaiver A biowaiver is an exemption from

conducting human bioequivalence studies when the active ingredient(s) meet certain solubility and permeability criteria in vitro and when the dissolution profile of the dosage form meets the requirements for an immediate release dosage form

Waiver of In Vivo Bioequivalence Study based on

Pharmaceutical Dosage Form (Solutions)

Biopharmaceutics Classification System

Dose (Highest Strength should be tested)

BCS BIOWAIVER

Biowaiver for

Rapid and similar dissolution High solubility ampHigh permeability Wide therapeutic window Excipients used in dosage form used

previously in approved IR solid dosage forms

REQUEST FOR BIOWAIVERS

Data Supporting -

Rapid and Similar Dissolution

High Permeability

High Solubility

Limitations of BCS as a Predictor of Drug

DispositionΩ Permeability (90 absorption) is difficult to

determine and difficult to convince the regulatory agency

Ω There is little predictability for BCS classification drugs beyond Class 1 primarily due to the difficulty of determining and proving 90 absorption many drugs are misclassified (eg HIV protease inhibitors

as Class 4 compounds))

Conclusion BCS aims to provide a regulatory tool for

replacing certain BE studies by accurate in-vitro dissolution tests

This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in

drug molecules with a sufficiently high permeability solubility and dissolution

rate and that will automatically increase the importance of the BCS as

a regulatory tool over time

References Draft guidance for industry waiver of in vivo

bioavailability and bioequivalence studies for immediate release solid oral dosage forms containing certain active moieties active ingredients based on a biopharmaceutic classification system february 1999 CDERFDA

Amidon GL Lennernas H Shah VP Crison JRA A theoretical basis for a biopharmaceutic drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharm Res 12 413-420 (1995)

Guidance for industry immediate release solid oral dosage forms scale up and post approval changes november 1995 CDERFDA

Medicamento generico from website httpwwwAnvisaGo

Devane J Oral drug delivery technology addressing the solubility permeability paradigm pharm Technol 68-74 november 1998

Amidon G LLennernaumls H Shah V P And crisonj R A theoretical basis for a biopharmaceutics drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharmaceutical research 12 413-420 (1995)

Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA CDER 1997 1048603httpwwwfdagovcderguidance1713bp1pdf

Guidance for Industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System FDA CDER August 2000 httpwwwfdagovcderguidance3618fnlhtm

Thank you

• BIOPHARMACEUTICS CLASSIFICATION SYSTEM
• Contents
• Introduction
• Slide 4
• Slide 5
• Biopharmaceutics Classification System
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• DISSOLUTION DETERMINATION
• CLASS BOUNDARIES
• BCS Class Boundaries Objectives
• Slide 15
• BCS -Implications for drug development
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Applications of BCS in oral drug delivery technology
• Class II - High Permeability Low Solubility
• Slide 27
• Slide 28
• Biowaiver
• Waiver of In Vivo Bioequivalence Study based on
• BCS BIOWAIVER
• REQUEST FOR BIOWAIVERS
• Limitations of BCS as a Predictor of Drug Disposition
• Conclusion
• References
• Slide 36
• Slide 37

DISSOLUTION DETERMINATION

USP apparatus I (basket) at 100 rpm or USP apparatus II (paddle) at 50 rpm

Dissolution media (900 ml) 01 N HCl or simulated gastric fluid pH 45 buffer and pH 68 buffer or simulated intestinal fluid

Compare dissolution profiles of test and reference products using a similarity factor (f2)

0

CLASS BOUNDARIES

HIGHLY SOLUBLE the highest dose strength is soluble in lt 250 ml water over a pH range of 1 to 75

The volume estimate-a glassful (8 ounce)

HIGHLY PERMEABLE when the extent of absorption in humans is determined to be gt 90 of an administered dose

RAPIDLY DISSOLVING when gt 85 of the labeled amount of drug substance dissolves within 30 minutes using USP apparatus I or II in a volume of lt 900 ml buffer solutions

BCS Class Boundaries Objectives

Dissolution(Product)

Solubility (Drug)

Permeability

(Drug)

Rapid dissolution - ensure that in vivo dissolution is not likely to be theldquorate determiningrdquo step

High solubility- ensure that solubilityis not likely to limit dissolution and therefore absorption

High permeability - ensure that drugis completely absorbed during the limitedtransit time through the small intestine

BCS -Implications for drug developmentЖApplication in early drug development and then in

the management of product change through its life cycle

ЖAids fundamental understanding of the biopharmaceutical and physical properties of the drug

ЖAids discriminatory dissolution method development

ЖCan help guide the development of in-vitroin-vivo correlations

ЖCan be used to obtain a biowaiver

ЖDevelopment of poorly soluble drugs

This classification is associated with drug dissolution and absorption model which identifies the key parameters controlling drug absorption as a set of dimensionless numbers viz

BCS defines 3 numbers (no units)

An ~ absorption number Do ~ dose number Dn ~ dissolution number

ABS

GI

GI

eff

TT

TR

PAn

Effective permeability

Radius of GI

Residence time in GI

Time required forcomplete absorption

Absorption NumberA function of GI Permeability to Drug Substance

S

Water

CV

DDo

Highest Dose Unit

250 mL

Solubility

Dose NumberA function of solubility of drug substance

Solubility mgmL

DISS

GI

GI

S

TT

TC

rD

Dn2

3Diffusivity5x10-6 cm2s

Density12 mgcm3

Particle Radiusm

Residence time in GI 180 min

Time required forcomplete dissolution

Dissolution NumberA function of drug release from formulation

IVIVC expectations for immediate release products based on BCS

Class Solubility Permeability Absorption rate control

IVIVC expectations for Immediate release product

I High High Gastric emptying

IVIVC expected if dissolution rate is slower than gastric emptying rate otherwise limited or no correlations

II Low High Dissolution IVIVC expected if in vitro dissolution rate is similar to in vivo dissolution rate unless dose is very high

III High Low Permeability Absorption (permeability) is rate determining and limited or no IVIVC with dissolution

IV Low Low Case by case

Limited or no IVIVC is expected

High Solubility Low Solubility H

igh

Pe

rmea

bil

ity

Class 1 Abacavir Acetaminophen Acyclovirb AmilorideSI

Amitryptyline SI Antipyrine Atropine Buspironec Caffeine Captopril ChloroquineSI

Chlorpheniramine Cyclophosphamide Desipramine Diazepam Diltiazem SI Diphenhydramine Disopyramide Doxepin Doxycycline Enalapril Ephedrine Ergonovine Ethambutol Ethinyl Estradiol FluoxetineI

Glucose

ImipramineI Ketorolac Ketoprofen Labetolol LevodopaS Levofloxacin S LidocaineI Lomefloxacin Meperidine Metoprolol Metronidazole MidazolamSI Minocycline Misoprostol Nifedipine S Phenobarbital Phenylalanine Prednisolone PrimaquineS Promazine Propranolol I QuinidineSI Rosiglitazone Salicylic acid Theophylline Valproic acid Verapamil I Zidovudine

Class 2 Amiodarone I AtorvastatinS I AzithromycinS I

Carbamazepine SI Carvedilol Chlorpromazine I CisaprideS

Ciprofloxacin S Cyclosporine S I Danazol Dapsone Diclofenac Diflunisal Digoxin S Erythromycin SI Flurbiprofen Glipizide GlyburideSI Griseofulvin Ibuprofen Indinavir S

Indomethacin

Itraconazole SI Ketoconazole I LansoprazoleI Lovastatin SI Mebendazole Naproxen Nelfinavir SI Ofloxacin Oxaprozin Phenazopyridine PhenytoinS Piroxicam Raloxifene S Ritonavir SI Saquinavir SI Sirolimus S Spironolactone I Tacrolimus SI TalinololS

Tamoxifen I Terfenadine I Warfarin

High Solubility Low Solubility Lo

w P

erm

eabi

lity

Class 3 Acyclovir Amiloride SI Amoxicillin SI Atenolol Atropine Bisphosphonates Bidisomide Captopril Cefazolin Cetirizine Cimetidine S Ciprofloxacin S Cloxacillin Dicloxacillin S Erythromycin SI

Famotidine

Fexofenadine S Folinic acid Furosemide Ganciclovir Hydrochlorothiazide Lisinopril Metformin Methotrexate Nadolol Pravastatin S Penicillins Ranitidine S Tetracycline Trimethoprim S Valsartan Zalcitabine

Class 4 Amphotericin B Chlorthalidone Chlorothiazide Colistin Ciprofloxacin S Furosemide Hydrochlorothiazide Mebendazole Methotrexate Neomycin

Applications of BCS in oral drug delivery technology

Achieve a target release profile associated with a particular pharmacokinetic andor pharmacodynamic profile

Formulation approaches include both control of release rate and certain physicochemical properties of drugs like pH-solubility profile of drug

Class I - High Permeability High Solubility

Micronisation

Addition of surfactants

Formulation as emulsions and microemulsions systems

Use of complexing agents like cyclodextrins

Class II - High Permeability

Low Solubility

Require the technologies that address to fundamental limitations of absolute or regional permeability

Peptides and proteins constitute the part of class III and the technologies handling such materials are on rise now days

Class III - Low Permeability High Solubility

Class IV - Low Permeability Low Solubility

Major challenge for development of drug delivery system and the route of choice for administering such drugs is parenteral (solubility enhancers)

Fortunately extreme examples are the exception rather than the rule and are rarely developed and reach the market

Biowaiver A biowaiver is an exemption from

conducting human bioequivalence studies when the active ingredient(s) meet certain solubility and permeability criteria in vitro and when the dissolution profile of the dosage form meets the requirements for an immediate release dosage form

Waiver of In Vivo Bioequivalence Study based on

Pharmaceutical Dosage Form (Solutions)

Biopharmaceutics Classification System

Dose (Highest Strength should be tested)

BCS BIOWAIVER

Biowaiver for

Rapid and similar dissolution High solubility ampHigh permeability Wide therapeutic window Excipients used in dosage form used

previously in approved IR solid dosage forms

REQUEST FOR BIOWAIVERS

Data Supporting -

Rapid and Similar Dissolution

High Permeability

High Solubility

Limitations of BCS as a Predictor of Drug

DispositionΩ Permeability (90 absorption) is difficult to

determine and difficult to convince the regulatory agency

Ω There is little predictability for BCS classification drugs beyond Class 1 primarily due to the difficulty of determining and proving 90 absorption many drugs are misclassified (eg HIV protease inhibitors

as Class 4 compounds))

Conclusion BCS aims to provide a regulatory tool for

replacing certain BE studies by accurate in-vitro dissolution tests

This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in

drug molecules with a sufficiently high permeability solubility and dissolution

rate and that will automatically increase the importance of the BCS as

a regulatory tool over time

References Draft guidance for industry waiver of in vivo

bioavailability and bioequivalence studies for immediate release solid oral dosage forms containing certain active moieties active ingredients based on a biopharmaceutic classification system february 1999 CDERFDA

Amidon GL Lennernas H Shah VP Crison JRA A theoretical basis for a biopharmaceutic drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharm Res 12 413-420 (1995)

Guidance for industry immediate release solid oral dosage forms scale up and post approval changes november 1995 CDERFDA

Medicamento generico from website httpwwwAnvisaGo

Devane J Oral drug delivery technology addressing the solubility permeability paradigm pharm Technol 68-74 november 1998

Amidon G LLennernaumls H Shah V P And crisonj R A theoretical basis for a biopharmaceutics drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharmaceutical research 12 413-420 (1995)

Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA CDER 1997 1048603httpwwwfdagovcderguidance1713bp1pdf

Guidance for Industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System FDA CDER August 2000 httpwwwfdagovcderguidance3618fnlhtm

Thank you

• BIOPHARMACEUTICS CLASSIFICATION SYSTEM
• Contents
• Introduction
• Slide 4
• Slide 5
• Biopharmaceutics Classification System
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• DISSOLUTION DETERMINATION
• CLASS BOUNDARIES
• BCS Class Boundaries Objectives
• Slide 15
• BCS -Implications for drug development
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Applications of BCS in oral drug delivery technology
• Class II - High Permeability Low Solubility
• Slide 27
• Slide 28
• Biowaiver
• Waiver of In Vivo Bioequivalence Study based on
• BCS BIOWAIVER
• REQUEST FOR BIOWAIVERS
• Limitations of BCS as a Predictor of Drug Disposition
• Conclusion
• References
• Slide 36
• Slide 37

CLASS BOUNDARIES

HIGHLY SOLUBLE the highest dose strength is soluble in lt 250 ml water over a pH range of 1 to 75

The volume estimate-a glassful (8 ounce)

HIGHLY PERMEABLE when the extent of absorption in humans is determined to be gt 90 of an administered dose

RAPIDLY DISSOLVING when gt 85 of the labeled amount of drug substance dissolves within 30 minutes using USP apparatus I or II in a volume of lt 900 ml buffer solutions

BCS Class Boundaries Objectives

Dissolution(Product)

Solubility (Drug)

Permeability

(Drug)

Rapid dissolution - ensure that in vivo dissolution is not likely to be theldquorate determiningrdquo step

High solubility- ensure that solubilityis not likely to limit dissolution and therefore absorption

High permeability - ensure that drugis completely absorbed during the limitedtransit time through the small intestine

BCS -Implications for drug developmentЖApplication in early drug development and then in

the management of product change through its life cycle

ЖAids fundamental understanding of the biopharmaceutical and physical properties of the drug

ЖAids discriminatory dissolution method development

ЖCan help guide the development of in-vitroin-vivo correlations

ЖCan be used to obtain a biowaiver

ЖDevelopment of poorly soluble drugs

This classification is associated with drug dissolution and absorption model which identifies the key parameters controlling drug absorption as a set of dimensionless numbers viz

BCS defines 3 numbers (no units)

An ~ absorption number Do ~ dose number Dn ~ dissolution number

ABS

GI

GI

eff

TT

TR

PAn

Effective permeability

Radius of GI

Residence time in GI

Time required forcomplete absorption

Absorption NumberA function of GI Permeability to Drug Substance

S

Water

CV

DDo

Highest Dose Unit

250 mL

Solubility

Dose NumberA function of solubility of drug substance

Solubility mgmL

DISS

GI

GI

S

TT

TC

rD

Dn2

3Diffusivity5x10-6 cm2s

Density12 mgcm3

Particle Radiusm

Residence time in GI 180 min

Time required forcomplete dissolution

Dissolution NumberA function of drug release from formulation

IVIVC expectations for immediate release products based on BCS

Class Solubility Permeability Absorption rate control

IVIVC expectations for Immediate release product

I High High Gastric emptying

IVIVC expected if dissolution rate is slower than gastric emptying rate otherwise limited or no correlations

II Low High Dissolution IVIVC expected if in vitro dissolution rate is similar to in vivo dissolution rate unless dose is very high

III High Low Permeability Absorption (permeability) is rate determining and limited or no IVIVC with dissolution

IV Low Low Case by case

Limited or no IVIVC is expected

High Solubility Low Solubility H

igh

Pe

rmea

bil

ity

Class 1 Abacavir Acetaminophen Acyclovirb AmilorideSI

Amitryptyline SI Antipyrine Atropine Buspironec Caffeine Captopril ChloroquineSI

Chlorpheniramine Cyclophosphamide Desipramine Diazepam Diltiazem SI Diphenhydramine Disopyramide Doxepin Doxycycline Enalapril Ephedrine Ergonovine Ethambutol Ethinyl Estradiol FluoxetineI

Glucose

ImipramineI Ketorolac Ketoprofen Labetolol LevodopaS Levofloxacin S LidocaineI Lomefloxacin Meperidine Metoprolol Metronidazole MidazolamSI Minocycline Misoprostol Nifedipine S Phenobarbital Phenylalanine Prednisolone PrimaquineS Promazine Propranolol I QuinidineSI Rosiglitazone Salicylic acid Theophylline Valproic acid Verapamil I Zidovudine

Class 2 Amiodarone I AtorvastatinS I AzithromycinS I

Carbamazepine SI Carvedilol Chlorpromazine I CisaprideS

Ciprofloxacin S Cyclosporine S I Danazol Dapsone Diclofenac Diflunisal Digoxin S Erythromycin SI Flurbiprofen Glipizide GlyburideSI Griseofulvin Ibuprofen Indinavir S

Indomethacin

Itraconazole SI Ketoconazole I LansoprazoleI Lovastatin SI Mebendazole Naproxen Nelfinavir SI Ofloxacin Oxaprozin Phenazopyridine PhenytoinS Piroxicam Raloxifene S Ritonavir SI Saquinavir SI Sirolimus S Spironolactone I Tacrolimus SI TalinololS

Tamoxifen I Terfenadine I Warfarin

High Solubility Low Solubility Lo

w P

erm

eabi

lity

Class 3 Acyclovir Amiloride SI Amoxicillin SI Atenolol Atropine Bisphosphonates Bidisomide Captopril Cefazolin Cetirizine Cimetidine S Ciprofloxacin S Cloxacillin Dicloxacillin S Erythromycin SI

Famotidine

Fexofenadine S Folinic acid Furosemide Ganciclovir Hydrochlorothiazide Lisinopril Metformin Methotrexate Nadolol Pravastatin S Penicillins Ranitidine S Tetracycline Trimethoprim S Valsartan Zalcitabine

Class 4 Amphotericin B Chlorthalidone Chlorothiazide Colistin Ciprofloxacin S Furosemide Hydrochlorothiazide Mebendazole Methotrexate Neomycin

Applications of BCS in oral drug delivery technology

Achieve a target release profile associated with a particular pharmacokinetic andor pharmacodynamic profile

Formulation approaches include both control of release rate and certain physicochemical properties of drugs like pH-solubility profile of drug

Class I - High Permeability High Solubility

Micronisation

Addition of surfactants

Formulation as emulsions and microemulsions systems

Use of complexing agents like cyclodextrins

Class II - High Permeability

Low Solubility

Require the technologies that address to fundamental limitations of absolute or regional permeability

Peptides and proteins constitute the part of class III and the technologies handling such materials are on rise now days

Class III - Low Permeability High Solubility

Class IV - Low Permeability Low Solubility

Major challenge for development of drug delivery system and the route of choice for administering such drugs is parenteral (solubility enhancers)

Fortunately extreme examples are the exception rather than the rule and are rarely developed and reach the market

Biowaiver A biowaiver is an exemption from

conducting human bioequivalence studies when the active ingredient(s) meet certain solubility and permeability criteria in vitro and when the dissolution profile of the dosage form meets the requirements for an immediate release dosage form

Waiver of In Vivo Bioequivalence Study based on

Pharmaceutical Dosage Form (Solutions)

Biopharmaceutics Classification System

Dose (Highest Strength should be tested)

BCS BIOWAIVER

Biowaiver for

Rapid and similar dissolution High solubility ampHigh permeability Wide therapeutic window Excipients used in dosage form used

previously in approved IR solid dosage forms

REQUEST FOR BIOWAIVERS

Data Supporting -

Rapid and Similar Dissolution

High Permeability

High Solubility

Limitations of BCS as a Predictor of Drug

DispositionΩ Permeability (90 absorption) is difficult to

determine and difficult to convince the regulatory agency

Ω There is little predictability for BCS classification drugs beyond Class 1 primarily due to the difficulty of determining and proving 90 absorption many drugs are misclassified (eg HIV protease inhibitors

as Class 4 compounds))

Conclusion BCS aims to provide a regulatory tool for

replacing certain BE studies by accurate in-vitro dissolution tests

This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in

drug molecules with a sufficiently high permeability solubility and dissolution

rate and that will automatically increase the importance of the BCS as

a regulatory tool over time

References Draft guidance for industry waiver of in vivo

bioavailability and bioequivalence studies for immediate release solid oral dosage forms containing certain active moieties active ingredients based on a biopharmaceutic classification system february 1999 CDERFDA

Amidon GL Lennernas H Shah VP Crison JRA A theoretical basis for a biopharmaceutic drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharm Res 12 413-420 (1995)

Guidance for industry immediate release solid oral dosage forms scale up and post approval changes november 1995 CDERFDA

Medicamento generico from website httpwwwAnvisaGo

Devane J Oral drug delivery technology addressing the solubility permeability paradigm pharm Technol 68-74 november 1998

Amidon G LLennernaumls H Shah V P And crisonj R A theoretical basis for a biopharmaceutics drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharmaceutical research 12 413-420 (1995)

Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA CDER 1997 1048603httpwwwfdagovcderguidance1713bp1pdf

Guidance for Industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System FDA CDER August 2000 httpwwwfdagovcderguidance3618fnlhtm

Thank you

• BIOPHARMACEUTICS CLASSIFICATION SYSTEM
• Contents
• Introduction
• Slide 4
• Slide 5
• Biopharmaceutics Classification System
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• DISSOLUTION DETERMINATION
• CLASS BOUNDARIES
• BCS Class Boundaries Objectives
• Slide 15
• BCS -Implications for drug development
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Applications of BCS in oral drug delivery technology
• Class II - High Permeability Low Solubility
• Slide 27
• Slide 28
• Biowaiver
• Waiver of In Vivo Bioequivalence Study based on
• BCS BIOWAIVER
• REQUEST FOR BIOWAIVERS
• Limitations of BCS as a Predictor of Drug Disposition
• Conclusion
• References
• Slide 36
• Slide 37

BCS Class Boundaries Objectives

Dissolution(Product)

Solubility (Drug)

Permeability

(Drug)

Rapid dissolution - ensure that in vivo dissolution is not likely to be theldquorate determiningrdquo step

High solubility- ensure that solubilityis not likely to limit dissolution and therefore absorption

High permeability - ensure that drugis completely absorbed during the limitedtransit time through the small intestine

BCS -Implications for drug developmentЖApplication in early drug development and then in

the management of product change through its life cycle

ЖAids fundamental understanding of the biopharmaceutical and physical properties of the drug

ЖAids discriminatory dissolution method development

ЖCan help guide the development of in-vitroin-vivo correlations

ЖCan be used to obtain a biowaiver

ЖDevelopment of poorly soluble drugs

This classification is associated with drug dissolution and absorption model which identifies the key parameters controlling drug absorption as a set of dimensionless numbers viz

BCS defines 3 numbers (no units)

An ~ absorption number Do ~ dose number Dn ~ dissolution number

ABS

GI

GI

eff

TT

TR

PAn

Effective permeability

Radius of GI

Residence time in GI

Time required forcomplete absorption

Absorption NumberA function of GI Permeability to Drug Substance

S

Water

CV

DDo

Highest Dose Unit

250 mL

Solubility

Dose NumberA function of solubility of drug substance

Solubility mgmL

DISS

GI

GI

S

TT

TC

rD

Dn2

3Diffusivity5x10-6 cm2s

Density12 mgcm3

Particle Radiusm

Residence time in GI 180 min

Time required forcomplete dissolution

Dissolution NumberA function of drug release from formulation

IVIVC expectations for immediate release products based on BCS

Class Solubility Permeability Absorption rate control

IVIVC expectations for Immediate release product

I High High Gastric emptying

IVIVC expected if dissolution rate is slower than gastric emptying rate otherwise limited or no correlations

II Low High Dissolution IVIVC expected if in vitro dissolution rate is similar to in vivo dissolution rate unless dose is very high

III High Low Permeability Absorption (permeability) is rate determining and limited or no IVIVC with dissolution

IV Low Low Case by case

Limited or no IVIVC is expected

High Solubility Low Solubility H

igh

Pe

rmea

bil

ity

Class 1 Abacavir Acetaminophen Acyclovirb AmilorideSI

Amitryptyline SI Antipyrine Atropine Buspironec Caffeine Captopril ChloroquineSI

Chlorpheniramine Cyclophosphamide Desipramine Diazepam Diltiazem SI Diphenhydramine Disopyramide Doxepin Doxycycline Enalapril Ephedrine Ergonovine Ethambutol Ethinyl Estradiol FluoxetineI

Glucose

ImipramineI Ketorolac Ketoprofen Labetolol LevodopaS Levofloxacin S LidocaineI Lomefloxacin Meperidine Metoprolol Metronidazole MidazolamSI Minocycline Misoprostol Nifedipine S Phenobarbital Phenylalanine Prednisolone PrimaquineS Promazine Propranolol I QuinidineSI Rosiglitazone Salicylic acid Theophylline Valproic acid Verapamil I Zidovudine

Class 2 Amiodarone I AtorvastatinS I AzithromycinS I

Carbamazepine SI Carvedilol Chlorpromazine I CisaprideS

Ciprofloxacin S Cyclosporine S I Danazol Dapsone Diclofenac Diflunisal Digoxin S Erythromycin SI Flurbiprofen Glipizide GlyburideSI Griseofulvin Ibuprofen Indinavir S

Indomethacin

Itraconazole SI Ketoconazole I LansoprazoleI Lovastatin SI Mebendazole Naproxen Nelfinavir SI Ofloxacin Oxaprozin Phenazopyridine PhenytoinS Piroxicam Raloxifene S Ritonavir SI Saquinavir SI Sirolimus S Spironolactone I Tacrolimus SI TalinololS

Tamoxifen I Terfenadine I Warfarin

High Solubility Low Solubility Lo

w P

erm

eabi

lity

Class 3 Acyclovir Amiloride SI Amoxicillin SI Atenolol Atropine Bisphosphonates Bidisomide Captopril Cefazolin Cetirizine Cimetidine S Ciprofloxacin S Cloxacillin Dicloxacillin S Erythromycin SI

Famotidine

Fexofenadine S Folinic acid Furosemide Ganciclovir Hydrochlorothiazide Lisinopril Metformin Methotrexate Nadolol Pravastatin S Penicillins Ranitidine S Tetracycline Trimethoprim S Valsartan Zalcitabine

Class 4 Amphotericin B Chlorthalidone Chlorothiazide Colistin Ciprofloxacin S Furosemide Hydrochlorothiazide Mebendazole Methotrexate Neomycin

Applications of BCS in oral drug delivery technology

Achieve a target release profile associated with a particular pharmacokinetic andor pharmacodynamic profile

Formulation approaches include both control of release rate and certain physicochemical properties of drugs like pH-solubility profile of drug

Class I - High Permeability High Solubility

Micronisation

Addition of surfactants

Formulation as emulsions and microemulsions systems

Use of complexing agents like cyclodextrins

Class II - High Permeability

Low Solubility

Require the technologies that address to fundamental limitations of absolute or regional permeability

Peptides and proteins constitute the part of class III and the technologies handling such materials are on rise now days

Class III - Low Permeability High Solubility

Class IV - Low Permeability Low Solubility

Major challenge for development of drug delivery system and the route of choice for administering such drugs is parenteral (solubility enhancers)

Fortunately extreme examples are the exception rather than the rule and are rarely developed and reach the market

Biowaiver A biowaiver is an exemption from

conducting human bioequivalence studies when the active ingredient(s) meet certain solubility and permeability criteria in vitro and when the dissolution profile of the dosage form meets the requirements for an immediate release dosage form

Waiver of In Vivo Bioequivalence Study based on

Pharmaceutical Dosage Form (Solutions)

Biopharmaceutics Classification System

Dose (Highest Strength should be tested)

BCS BIOWAIVER

Biowaiver for

Rapid and similar dissolution High solubility ampHigh permeability Wide therapeutic window Excipients used in dosage form used

previously in approved IR solid dosage forms

REQUEST FOR BIOWAIVERS

Data Supporting -

Rapid and Similar Dissolution

High Permeability

High Solubility

Limitations of BCS as a Predictor of Drug

DispositionΩ Permeability (90 absorption) is difficult to

determine and difficult to convince the regulatory agency

Ω There is little predictability for BCS classification drugs beyond Class 1 primarily due to the difficulty of determining and proving 90 absorption many drugs are misclassified (eg HIV protease inhibitors

as Class 4 compounds))

Conclusion BCS aims to provide a regulatory tool for

replacing certain BE studies by accurate in-vitro dissolution tests

This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in

drug molecules with a sufficiently high permeability solubility and dissolution

rate and that will automatically increase the importance of the BCS as

a regulatory tool over time

References Draft guidance for industry waiver of in vivo

bioavailability and bioequivalence studies for immediate release solid oral dosage forms containing certain active moieties active ingredients based on a biopharmaceutic classification system february 1999 CDERFDA

Amidon GL Lennernas H Shah VP Crison JRA A theoretical basis for a biopharmaceutic drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharm Res 12 413-420 (1995)

Guidance for industry immediate release solid oral dosage forms scale up and post approval changes november 1995 CDERFDA

Medicamento generico from website httpwwwAnvisaGo

Devane J Oral drug delivery technology addressing the solubility permeability paradigm pharm Technol 68-74 november 1998

Amidon G LLennernaumls H Shah V P And crisonj R A theoretical basis for a biopharmaceutics drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharmaceutical research 12 413-420 (1995)

Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA CDER 1997 1048603httpwwwfdagovcderguidance1713bp1pdf

Guidance for Industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System FDA CDER August 2000 httpwwwfdagovcderguidance3618fnlhtm

Thank you

• BIOPHARMACEUTICS CLASSIFICATION SYSTEM
• Contents
• Introduction
• Slide 4
• Slide 5
• Biopharmaceutics Classification System
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• DISSOLUTION DETERMINATION
• CLASS BOUNDARIES
• BCS Class Boundaries Objectives
• Slide 15
• BCS -Implications for drug development
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Applications of BCS in oral drug delivery technology
• Class II - High Permeability Low Solubility
• Slide 27
• Slide 28
• Biowaiver
• Waiver of In Vivo Bioequivalence Study based on
• BCS BIOWAIVER
• REQUEST FOR BIOWAIVERS
• Limitations of BCS as a Predictor of Drug Disposition
• Conclusion
• References
• Slide 36
• Slide 37

BCS -Implications for drug developmentЖApplication in early drug development and then in

the management of product change through its life cycle

ЖAids fundamental understanding of the biopharmaceutical and physical properties of the drug

ЖAids discriminatory dissolution method development

ЖCan help guide the development of in-vitroin-vivo correlations

ЖCan be used to obtain a biowaiver

ЖDevelopment of poorly soluble drugs

This classification is associated with drug dissolution and absorption model which identifies the key parameters controlling drug absorption as a set of dimensionless numbers viz

BCS defines 3 numbers (no units)

An ~ absorption number Do ~ dose number Dn ~ dissolution number

ABS

GI

GI

eff

TT

TR

PAn

Effective permeability

Radius of GI

Residence time in GI

Time required forcomplete absorption

Absorption NumberA function of GI Permeability to Drug Substance

S

Water

CV

DDo

Highest Dose Unit

250 mL

Solubility

Dose NumberA function of solubility of drug substance

Solubility mgmL

DISS

GI

GI

S

TT

TC

rD

Dn2

3Diffusivity5x10-6 cm2s

Density12 mgcm3

Particle Radiusm

Residence time in GI 180 min

Time required forcomplete dissolution

Dissolution NumberA function of drug release from formulation

IVIVC expectations for immediate release products based on BCS

Class Solubility Permeability Absorption rate control

IVIVC expectations for Immediate release product

I High High Gastric emptying

IVIVC expected if dissolution rate is slower than gastric emptying rate otherwise limited or no correlations

II Low High Dissolution IVIVC expected if in vitro dissolution rate is similar to in vivo dissolution rate unless dose is very high

III High Low Permeability Absorption (permeability) is rate determining and limited or no IVIVC with dissolution

IV Low Low Case by case

Limited or no IVIVC is expected

High Solubility Low Solubility H

igh

Pe

rmea

bil

ity

Class 1 Abacavir Acetaminophen Acyclovirb AmilorideSI

Amitryptyline SI Antipyrine Atropine Buspironec Caffeine Captopril ChloroquineSI

Chlorpheniramine Cyclophosphamide Desipramine Diazepam Diltiazem SI Diphenhydramine Disopyramide Doxepin Doxycycline Enalapril Ephedrine Ergonovine Ethambutol Ethinyl Estradiol FluoxetineI

Glucose

ImipramineI Ketorolac Ketoprofen Labetolol LevodopaS Levofloxacin S LidocaineI Lomefloxacin Meperidine Metoprolol Metronidazole MidazolamSI Minocycline Misoprostol Nifedipine S Phenobarbital Phenylalanine Prednisolone PrimaquineS Promazine Propranolol I QuinidineSI Rosiglitazone Salicylic acid Theophylline Valproic acid Verapamil I Zidovudine

Class 2 Amiodarone I AtorvastatinS I AzithromycinS I

Carbamazepine SI Carvedilol Chlorpromazine I CisaprideS

Ciprofloxacin S Cyclosporine S I Danazol Dapsone Diclofenac Diflunisal Digoxin S Erythromycin SI Flurbiprofen Glipizide GlyburideSI Griseofulvin Ibuprofen Indinavir S

Indomethacin

Itraconazole SI Ketoconazole I LansoprazoleI Lovastatin SI Mebendazole Naproxen Nelfinavir SI Ofloxacin Oxaprozin Phenazopyridine PhenytoinS Piroxicam Raloxifene S Ritonavir SI Saquinavir SI Sirolimus S Spironolactone I Tacrolimus SI TalinololS

Tamoxifen I Terfenadine I Warfarin

High Solubility Low Solubility Lo

w P

erm

eabi

lity

Class 3 Acyclovir Amiloride SI Amoxicillin SI Atenolol Atropine Bisphosphonates Bidisomide Captopril Cefazolin Cetirizine Cimetidine S Ciprofloxacin S Cloxacillin Dicloxacillin S Erythromycin SI

Famotidine

Fexofenadine S Folinic acid Furosemide Ganciclovir Hydrochlorothiazide Lisinopril Metformin Methotrexate Nadolol Pravastatin S Penicillins Ranitidine S Tetracycline Trimethoprim S Valsartan Zalcitabine

Class 4 Amphotericin B Chlorthalidone Chlorothiazide Colistin Ciprofloxacin S Furosemide Hydrochlorothiazide Mebendazole Methotrexate Neomycin

Applications of BCS in oral drug delivery technology

Achieve a target release profile associated with a particular pharmacokinetic andor pharmacodynamic profile

Formulation approaches include both control of release rate and certain physicochemical properties of drugs like pH-solubility profile of drug

Class I - High Permeability High Solubility

Micronisation

Addition of surfactants

Formulation as emulsions and microemulsions systems

Use of complexing agents like cyclodextrins

Class II - High Permeability

Low Solubility

Require the technologies that address to fundamental limitations of absolute or regional permeability

Peptides and proteins constitute the part of class III and the technologies handling such materials are on rise now days

Class III - Low Permeability High Solubility

Class IV - Low Permeability Low Solubility

Major challenge for development of drug delivery system and the route of choice for administering such drugs is parenteral (solubility enhancers)

Fortunately extreme examples are the exception rather than the rule and are rarely developed and reach the market

Biowaiver A biowaiver is an exemption from

conducting human bioequivalence studies when the active ingredient(s) meet certain solubility and permeability criteria in vitro and when the dissolution profile of the dosage form meets the requirements for an immediate release dosage form

Waiver of In Vivo Bioequivalence Study based on

Pharmaceutical Dosage Form (Solutions)

Biopharmaceutics Classification System

Dose (Highest Strength should be tested)

BCS BIOWAIVER

Biowaiver for

Rapid and similar dissolution High solubility ampHigh permeability Wide therapeutic window Excipients used in dosage form used

previously in approved IR solid dosage forms

REQUEST FOR BIOWAIVERS

Data Supporting -

Rapid and Similar Dissolution

High Permeability

High Solubility

Limitations of BCS as a Predictor of Drug

DispositionΩ Permeability (90 absorption) is difficult to

determine and difficult to convince the regulatory agency

Ω There is little predictability for BCS classification drugs beyond Class 1 primarily due to the difficulty of determining and proving 90 absorption many drugs are misclassified (eg HIV protease inhibitors

as Class 4 compounds))

Conclusion BCS aims to provide a regulatory tool for

replacing certain BE studies by accurate in-vitro dissolution tests

This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in

drug molecules with a sufficiently high permeability solubility and dissolution

rate and that will automatically increase the importance of the BCS as

a regulatory tool over time

References Draft guidance for industry waiver of in vivo

bioavailability and bioequivalence studies for immediate release solid oral dosage forms containing certain active moieties active ingredients based on a biopharmaceutic classification system february 1999 CDERFDA

Amidon GL Lennernas H Shah VP Crison JRA A theoretical basis for a biopharmaceutic drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharm Res 12 413-420 (1995)

Guidance for industry immediate release solid oral dosage forms scale up and post approval changes november 1995 CDERFDA

Medicamento generico from website httpwwwAnvisaGo

Devane J Oral drug delivery technology addressing the solubility permeability paradigm pharm Technol 68-74 november 1998

Amidon G LLennernaumls H Shah V P And crisonj R A theoretical basis for a biopharmaceutics drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharmaceutical research 12 413-420 (1995)

Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA CDER 1997 1048603httpwwwfdagovcderguidance1713bp1pdf

Guidance for Industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System FDA CDER August 2000 httpwwwfdagovcderguidance3618fnlhtm

Thank you

• BIOPHARMACEUTICS CLASSIFICATION SYSTEM
• Contents
• Introduction
• Slide 4
• Slide 5
• Biopharmaceutics Classification System
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• DISSOLUTION DETERMINATION
• CLASS BOUNDARIES
• BCS Class Boundaries Objectives
• Slide 15
• BCS -Implications for drug development
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Applications of BCS in oral drug delivery technology
• Class II - High Permeability Low Solubility
• Slide 27
• Slide 28
• Biowaiver
• Waiver of In Vivo Bioequivalence Study based on
• BCS BIOWAIVER
• REQUEST FOR BIOWAIVERS
• Limitations of BCS as a Predictor of Drug Disposition
• Conclusion
• References
• Slide 36
• Slide 37

This classification is associated with drug dissolution and absorption model which identifies the key parameters controlling drug absorption as a set of dimensionless numbers viz

BCS defines 3 numbers (no units)

An ~ absorption number Do ~ dose number Dn ~ dissolution number

ABS

GI

GI

eff

TT

TR

PAn

Effective permeability

Radius of GI

Residence time in GI

Time required forcomplete absorption

Absorption NumberA function of GI Permeability to Drug Substance

S

Water

CV

DDo

Highest Dose Unit

250 mL

Solubility

Dose NumberA function of solubility of drug substance

Solubility mgmL

DISS

GI

GI

S

TT

TC

rD

Dn2

3Diffusivity5x10-6 cm2s

Density12 mgcm3

Particle Radiusm

Residence time in GI 180 min

Time required forcomplete dissolution

Dissolution NumberA function of drug release from formulation

IVIVC expectations for immediate release products based on BCS

Class Solubility Permeability Absorption rate control

IVIVC expectations for Immediate release product

I High High Gastric emptying

IVIVC expected if dissolution rate is slower than gastric emptying rate otherwise limited or no correlations

II Low High Dissolution IVIVC expected if in vitro dissolution rate is similar to in vivo dissolution rate unless dose is very high

III High Low Permeability Absorption (permeability) is rate determining and limited or no IVIVC with dissolution

IV Low Low Case by case

Limited or no IVIVC is expected

High Solubility Low Solubility H

igh

Pe

rmea

bil

ity

Class 1 Abacavir Acetaminophen Acyclovirb AmilorideSI

Amitryptyline SI Antipyrine Atropine Buspironec Caffeine Captopril ChloroquineSI

Chlorpheniramine Cyclophosphamide Desipramine Diazepam Diltiazem SI Diphenhydramine Disopyramide Doxepin Doxycycline Enalapril Ephedrine Ergonovine Ethambutol Ethinyl Estradiol FluoxetineI

Glucose

ImipramineI Ketorolac Ketoprofen Labetolol LevodopaS Levofloxacin S LidocaineI Lomefloxacin Meperidine Metoprolol Metronidazole MidazolamSI Minocycline Misoprostol Nifedipine S Phenobarbital Phenylalanine Prednisolone PrimaquineS Promazine Propranolol I QuinidineSI Rosiglitazone Salicylic acid Theophylline Valproic acid Verapamil I Zidovudine

Class 2 Amiodarone I AtorvastatinS I AzithromycinS I

Carbamazepine SI Carvedilol Chlorpromazine I CisaprideS

Ciprofloxacin S Cyclosporine S I Danazol Dapsone Diclofenac Diflunisal Digoxin S Erythromycin SI Flurbiprofen Glipizide GlyburideSI Griseofulvin Ibuprofen Indinavir S

Indomethacin

Itraconazole SI Ketoconazole I LansoprazoleI Lovastatin SI Mebendazole Naproxen Nelfinavir SI Ofloxacin Oxaprozin Phenazopyridine PhenytoinS Piroxicam Raloxifene S Ritonavir SI Saquinavir SI Sirolimus S Spironolactone I Tacrolimus SI TalinololS

Tamoxifen I Terfenadine I Warfarin

High Solubility Low Solubility Lo

w P

erm

eabi

lity

Class 3 Acyclovir Amiloride SI Amoxicillin SI Atenolol Atropine Bisphosphonates Bidisomide Captopril Cefazolin Cetirizine Cimetidine S Ciprofloxacin S Cloxacillin Dicloxacillin S Erythromycin SI

Famotidine

Fexofenadine S Folinic acid Furosemide Ganciclovir Hydrochlorothiazide Lisinopril Metformin Methotrexate Nadolol Pravastatin S Penicillins Ranitidine S Tetracycline Trimethoprim S Valsartan Zalcitabine

Class 4 Amphotericin B Chlorthalidone Chlorothiazide Colistin Ciprofloxacin S Furosemide Hydrochlorothiazide Mebendazole Methotrexate Neomycin

Applications of BCS in oral drug delivery technology

Achieve a target release profile associated with a particular pharmacokinetic andor pharmacodynamic profile

Formulation approaches include both control of release rate and certain physicochemical properties of drugs like pH-solubility profile of drug

Class I - High Permeability High Solubility

Micronisation

Addition of surfactants

Formulation as emulsions and microemulsions systems

Use of complexing agents like cyclodextrins

Class II - High Permeability

Low Solubility

Require the technologies that address to fundamental limitations of absolute or regional permeability

Peptides and proteins constitute the part of class III and the technologies handling such materials are on rise now days

Class III - Low Permeability High Solubility

Class IV - Low Permeability Low Solubility

Major challenge for development of drug delivery system and the route of choice for administering such drugs is parenteral (solubility enhancers)

Fortunately extreme examples are the exception rather than the rule and are rarely developed and reach the market

Biowaiver A biowaiver is an exemption from

conducting human bioequivalence studies when the active ingredient(s) meet certain solubility and permeability criteria in vitro and when the dissolution profile of the dosage form meets the requirements for an immediate release dosage form

Waiver of In Vivo Bioequivalence Study based on

Pharmaceutical Dosage Form (Solutions)

Biopharmaceutics Classification System

Dose (Highest Strength should be tested)

BCS BIOWAIVER

Biowaiver for

Rapid and similar dissolution High solubility ampHigh permeability Wide therapeutic window Excipients used in dosage form used

previously in approved IR solid dosage forms

REQUEST FOR BIOWAIVERS

Data Supporting -

Rapid and Similar Dissolution

High Permeability

High Solubility

Limitations of BCS as a Predictor of Drug

DispositionΩ Permeability (90 absorption) is difficult to

determine and difficult to convince the regulatory agency

Ω There is little predictability for BCS classification drugs beyond Class 1 primarily due to the difficulty of determining and proving 90 absorption many drugs are misclassified (eg HIV protease inhibitors

as Class 4 compounds))

Conclusion BCS aims to provide a regulatory tool for

replacing certain BE studies by accurate in-vitro dissolution tests

This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in

drug molecules with a sufficiently high permeability solubility and dissolution

rate and that will automatically increase the importance of the BCS as

a regulatory tool over time

References Draft guidance for industry waiver of in vivo

bioavailability and bioequivalence studies for immediate release solid oral dosage forms containing certain active moieties active ingredients based on a biopharmaceutic classification system february 1999 CDERFDA

Amidon GL Lennernas H Shah VP Crison JRA A theoretical basis for a biopharmaceutic drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharm Res 12 413-420 (1995)

Guidance for industry immediate release solid oral dosage forms scale up and post approval changes november 1995 CDERFDA

Medicamento generico from website httpwwwAnvisaGo

Devane J Oral drug delivery technology addressing the solubility permeability paradigm pharm Technol 68-74 november 1998

Amidon G LLennernaumls H Shah V P And crisonj R A theoretical basis for a biopharmaceutics drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharmaceutical research 12 413-420 (1995)

Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA CDER 1997 1048603httpwwwfdagovcderguidance1713bp1pdf

Guidance for Industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System FDA CDER August 2000 httpwwwfdagovcderguidance3618fnlhtm

Thank you

• BIOPHARMACEUTICS CLASSIFICATION SYSTEM
• Contents
• Introduction
• Slide 4
• Slide 5
• Biopharmaceutics Classification System
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• DISSOLUTION DETERMINATION
• CLASS BOUNDARIES
• BCS Class Boundaries Objectives
• Slide 15
• BCS -Implications for drug development
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Applications of BCS in oral drug delivery technology
• Class II - High Permeability Low Solubility
• Slide 27
• Slide 28
• Biowaiver
• Waiver of In Vivo Bioequivalence Study based on
• BCS BIOWAIVER
• REQUEST FOR BIOWAIVERS
• Limitations of BCS as a Predictor of Drug Disposition
• Conclusion
• References
• Slide 36
• Slide 37

ABS

GI

GI

eff

TT

TR

PAn

Effective permeability

Radius of GI

Residence time in GI

Time required forcomplete absorption

Absorption NumberA function of GI Permeability to Drug Substance

S

Water

CV

DDo

Highest Dose Unit

250 mL

Solubility

Dose NumberA function of solubility of drug substance

Solubility mgmL

DISS

GI

GI

S

TT

TC

rD

Dn2

3Diffusivity5x10-6 cm2s

Density12 mgcm3

Particle Radiusm

Residence time in GI 180 min

Time required forcomplete dissolution

Dissolution NumberA function of drug release from formulation

IVIVC expectations for immediate release products based on BCS

Class Solubility Permeability Absorption rate control

IVIVC expectations for Immediate release product

I High High Gastric emptying

IVIVC expected if dissolution rate is slower than gastric emptying rate otherwise limited or no correlations

II Low High Dissolution IVIVC expected if in vitro dissolution rate is similar to in vivo dissolution rate unless dose is very high

III High Low Permeability Absorption (permeability) is rate determining and limited or no IVIVC with dissolution

IV Low Low Case by case

Limited or no IVIVC is expected

High Solubility Low Solubility H

igh

Pe

rmea

bil

ity

Class 1 Abacavir Acetaminophen Acyclovirb AmilorideSI

Amitryptyline SI Antipyrine Atropine Buspironec Caffeine Captopril ChloroquineSI

Chlorpheniramine Cyclophosphamide Desipramine Diazepam Diltiazem SI Diphenhydramine Disopyramide Doxepin Doxycycline Enalapril Ephedrine Ergonovine Ethambutol Ethinyl Estradiol FluoxetineI

Glucose

ImipramineI Ketorolac Ketoprofen Labetolol LevodopaS Levofloxacin S LidocaineI Lomefloxacin Meperidine Metoprolol Metronidazole MidazolamSI Minocycline Misoprostol Nifedipine S Phenobarbital Phenylalanine Prednisolone PrimaquineS Promazine Propranolol I QuinidineSI Rosiglitazone Salicylic acid Theophylline Valproic acid Verapamil I Zidovudine

Class 2 Amiodarone I AtorvastatinS I AzithromycinS I

Carbamazepine SI Carvedilol Chlorpromazine I CisaprideS

Ciprofloxacin S Cyclosporine S I Danazol Dapsone Diclofenac Diflunisal Digoxin S Erythromycin SI Flurbiprofen Glipizide GlyburideSI Griseofulvin Ibuprofen Indinavir S

Indomethacin

Itraconazole SI Ketoconazole I LansoprazoleI Lovastatin SI Mebendazole Naproxen Nelfinavir SI Ofloxacin Oxaprozin Phenazopyridine PhenytoinS Piroxicam Raloxifene S Ritonavir SI Saquinavir SI Sirolimus S Spironolactone I Tacrolimus SI TalinololS

Tamoxifen I Terfenadine I Warfarin

High Solubility Low Solubility Lo

w P

erm

eabi

lity

Class 3 Acyclovir Amiloride SI Amoxicillin SI Atenolol Atropine Bisphosphonates Bidisomide Captopril Cefazolin Cetirizine Cimetidine S Ciprofloxacin S Cloxacillin Dicloxacillin S Erythromycin SI

Famotidine

Fexofenadine S Folinic acid Furosemide Ganciclovir Hydrochlorothiazide Lisinopril Metformin Methotrexate Nadolol Pravastatin S Penicillins Ranitidine S Tetracycline Trimethoprim S Valsartan Zalcitabine

Class 4 Amphotericin B Chlorthalidone Chlorothiazide Colistin Ciprofloxacin S Furosemide Hydrochlorothiazide Mebendazole Methotrexate Neomycin

Applications of BCS in oral drug delivery technology

Achieve a target release profile associated with a particular pharmacokinetic andor pharmacodynamic profile

Formulation approaches include both control of release rate and certain physicochemical properties of drugs like pH-solubility profile of drug

Class I - High Permeability High Solubility

Micronisation

Addition of surfactants

Formulation as emulsions and microemulsions systems

Use of complexing agents like cyclodextrins

Class II - High Permeability

Low Solubility

Require the technologies that address to fundamental limitations of absolute or regional permeability

Peptides and proteins constitute the part of class III and the technologies handling such materials are on rise now days

Class III - Low Permeability High Solubility

Class IV - Low Permeability Low Solubility

Major challenge for development of drug delivery system and the route of choice for administering such drugs is parenteral (solubility enhancers)

Fortunately extreme examples are the exception rather than the rule and are rarely developed and reach the market

Biowaiver A biowaiver is an exemption from

conducting human bioequivalence studies when the active ingredient(s) meet certain solubility and permeability criteria in vitro and when the dissolution profile of the dosage form meets the requirements for an immediate release dosage form

Waiver of In Vivo Bioequivalence Study based on

Pharmaceutical Dosage Form (Solutions)

Biopharmaceutics Classification System

Dose (Highest Strength should be tested)

BCS BIOWAIVER

Biowaiver for

Rapid and similar dissolution High solubility ampHigh permeability Wide therapeutic window Excipients used in dosage form used

previously in approved IR solid dosage forms

REQUEST FOR BIOWAIVERS

Data Supporting -

Rapid and Similar Dissolution

High Permeability

High Solubility

Limitations of BCS as a Predictor of Drug

DispositionΩ Permeability (90 absorption) is difficult to

determine and difficult to convince the regulatory agency

Ω There is little predictability for BCS classification drugs beyond Class 1 primarily due to the difficulty of determining and proving 90 absorption many drugs are misclassified (eg HIV protease inhibitors

as Class 4 compounds))

Conclusion BCS aims to provide a regulatory tool for

replacing certain BE studies by accurate in-vitro dissolution tests

This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in

drug molecules with a sufficiently high permeability solubility and dissolution

rate and that will automatically increase the importance of the BCS as

a regulatory tool over time

References Draft guidance for industry waiver of in vivo

bioavailability and bioequivalence studies for immediate release solid oral dosage forms containing certain active moieties active ingredients based on a biopharmaceutic classification system february 1999 CDERFDA

Amidon GL Lennernas H Shah VP Crison JRA A theoretical basis for a biopharmaceutic drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharm Res 12 413-420 (1995)

Guidance for industry immediate release solid oral dosage forms scale up and post approval changes november 1995 CDERFDA

Medicamento generico from website httpwwwAnvisaGo

Devane J Oral drug delivery technology addressing the solubility permeability paradigm pharm Technol 68-74 november 1998

Amidon G LLennernaumls H Shah V P And crisonj R A theoretical basis for a biopharmaceutics drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharmaceutical research 12 413-420 (1995)

Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA CDER 1997 1048603httpwwwfdagovcderguidance1713bp1pdf

Guidance for Industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System FDA CDER August 2000 httpwwwfdagovcderguidance3618fnlhtm

Thank you

• BIOPHARMACEUTICS CLASSIFICATION SYSTEM
• Contents
• Introduction
• Slide 4
• Slide 5
• Biopharmaceutics Classification System
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• DISSOLUTION DETERMINATION
• CLASS BOUNDARIES
• BCS Class Boundaries Objectives
• Slide 15
• BCS -Implications for drug development
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Applications of BCS in oral drug delivery technology
• Class II - High Permeability Low Solubility
• Slide 27
• Slide 28
• Biowaiver
• Waiver of In Vivo Bioequivalence Study based on
• BCS BIOWAIVER
• REQUEST FOR BIOWAIVERS
• Limitations of BCS as a Predictor of Drug Disposition
• Conclusion
• References
• Slide 36
• Slide 37

S

Water

CV

DDo

Highest Dose Unit

250 mL

Solubility

Dose NumberA function of solubility of drug substance

Solubility mgmL

DISS

GI

GI

S

TT

TC

rD

Dn2

3Diffusivity5x10-6 cm2s

Density12 mgcm3

Particle Radiusm

Residence time in GI 180 min

Time required forcomplete dissolution

Dissolution NumberA function of drug release from formulation

IVIVC expectations for immediate release products based on BCS

Class Solubility Permeability Absorption rate control

IVIVC expectations for Immediate release product

I High High Gastric emptying

IVIVC expected if dissolution rate is slower than gastric emptying rate otherwise limited or no correlations

II Low High Dissolution IVIVC expected if in vitro dissolution rate is similar to in vivo dissolution rate unless dose is very high

III High Low Permeability Absorption (permeability) is rate determining and limited or no IVIVC with dissolution

IV Low Low Case by case

Limited or no IVIVC is expected

High Solubility Low Solubility H

igh

Pe

rmea

bil

ity

Class 1 Abacavir Acetaminophen Acyclovirb AmilorideSI

Amitryptyline SI Antipyrine Atropine Buspironec Caffeine Captopril ChloroquineSI

Chlorpheniramine Cyclophosphamide Desipramine Diazepam Diltiazem SI Diphenhydramine Disopyramide Doxepin Doxycycline Enalapril Ephedrine Ergonovine Ethambutol Ethinyl Estradiol FluoxetineI

Glucose

ImipramineI Ketorolac Ketoprofen Labetolol LevodopaS Levofloxacin S LidocaineI Lomefloxacin Meperidine Metoprolol Metronidazole MidazolamSI Minocycline Misoprostol Nifedipine S Phenobarbital Phenylalanine Prednisolone PrimaquineS Promazine Propranolol I QuinidineSI Rosiglitazone Salicylic acid Theophylline Valproic acid Verapamil I Zidovudine

Class 2 Amiodarone I AtorvastatinS I AzithromycinS I

Carbamazepine SI Carvedilol Chlorpromazine I CisaprideS

Ciprofloxacin S Cyclosporine S I Danazol Dapsone Diclofenac Diflunisal Digoxin S Erythromycin SI Flurbiprofen Glipizide GlyburideSI Griseofulvin Ibuprofen Indinavir S

Indomethacin

Itraconazole SI Ketoconazole I LansoprazoleI Lovastatin SI Mebendazole Naproxen Nelfinavir SI Ofloxacin Oxaprozin Phenazopyridine PhenytoinS Piroxicam Raloxifene S Ritonavir SI Saquinavir SI Sirolimus S Spironolactone I Tacrolimus SI TalinololS

Tamoxifen I Terfenadine I Warfarin

High Solubility Low Solubility Lo

w P

erm

eabi

lity

Class 3 Acyclovir Amiloride SI Amoxicillin SI Atenolol Atropine Bisphosphonates Bidisomide Captopril Cefazolin Cetirizine Cimetidine S Ciprofloxacin S Cloxacillin Dicloxacillin S Erythromycin SI

Famotidine

Fexofenadine S Folinic acid Furosemide Ganciclovir Hydrochlorothiazide Lisinopril Metformin Methotrexate Nadolol Pravastatin S Penicillins Ranitidine S Tetracycline Trimethoprim S Valsartan Zalcitabine

Class 4 Amphotericin B Chlorthalidone Chlorothiazide Colistin Ciprofloxacin S Furosemide Hydrochlorothiazide Mebendazole Methotrexate Neomycin

Applications of BCS in oral drug delivery technology

Achieve a target release profile associated with a particular pharmacokinetic andor pharmacodynamic profile

Formulation approaches include both control of release rate and certain physicochemical properties of drugs like pH-solubility profile of drug

Class I - High Permeability High Solubility

Micronisation

Addition of surfactants

Formulation as emulsions and microemulsions systems

Use of complexing agents like cyclodextrins

Class II - High Permeability

Low Solubility

Require the technologies that address to fundamental limitations of absolute or regional permeability

Peptides and proteins constitute the part of class III and the technologies handling such materials are on rise now days

Class III - Low Permeability High Solubility

Class IV - Low Permeability Low Solubility

Major challenge for development of drug delivery system and the route of choice for administering such drugs is parenteral (solubility enhancers)

Fortunately extreme examples are the exception rather than the rule and are rarely developed and reach the market

Biowaiver A biowaiver is an exemption from

conducting human bioequivalence studies when the active ingredient(s) meet certain solubility and permeability criteria in vitro and when the dissolution profile of the dosage form meets the requirements for an immediate release dosage form

Waiver of In Vivo Bioequivalence Study based on

Pharmaceutical Dosage Form (Solutions)

Biopharmaceutics Classification System

Dose (Highest Strength should be tested)

BCS BIOWAIVER

Biowaiver for

Rapid and similar dissolution High solubility ampHigh permeability Wide therapeutic window Excipients used in dosage form used

previously in approved IR solid dosage forms

REQUEST FOR BIOWAIVERS

Data Supporting -

Rapid and Similar Dissolution

High Permeability

High Solubility

Limitations of BCS as a Predictor of Drug

DispositionΩ Permeability (90 absorption) is difficult to

determine and difficult to convince the regulatory agency

Ω There is little predictability for BCS classification drugs beyond Class 1 primarily due to the difficulty of determining and proving 90 absorption many drugs are misclassified (eg HIV protease inhibitors

as Class 4 compounds))

Conclusion BCS aims to provide a regulatory tool for

replacing certain BE studies by accurate in-vitro dissolution tests

This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in

drug molecules with a sufficiently high permeability solubility and dissolution

rate and that will automatically increase the importance of the BCS as

a regulatory tool over time

References Draft guidance for industry waiver of in vivo

bioavailability and bioequivalence studies for immediate release solid oral dosage forms containing certain active moieties active ingredients based on a biopharmaceutic classification system february 1999 CDERFDA

Amidon GL Lennernas H Shah VP Crison JRA A theoretical basis for a biopharmaceutic drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharm Res 12 413-420 (1995)

Guidance for industry immediate release solid oral dosage forms scale up and post approval changes november 1995 CDERFDA

Medicamento generico from website httpwwwAnvisaGo

Devane J Oral drug delivery technology addressing the solubility permeability paradigm pharm Technol 68-74 november 1998

Amidon G LLennernaumls H Shah V P And crisonj R A theoretical basis for a biopharmaceutics drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharmaceutical research 12 413-420 (1995)

Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA CDER 1997 1048603httpwwwfdagovcderguidance1713bp1pdf

Guidance for Industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System FDA CDER August 2000 httpwwwfdagovcderguidance3618fnlhtm

Thank you

• BIOPHARMACEUTICS CLASSIFICATION SYSTEM
• Contents
• Introduction
• Slide 4
• Slide 5
• Biopharmaceutics Classification System
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• DISSOLUTION DETERMINATION
• CLASS BOUNDARIES
• BCS Class Boundaries Objectives
• Slide 15
• BCS -Implications for drug development
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Applications of BCS in oral drug delivery technology
• Class II - High Permeability Low Solubility
• Slide 27
• Slide 28
• Biowaiver
• Waiver of In Vivo Bioequivalence Study based on
• BCS BIOWAIVER
• REQUEST FOR BIOWAIVERS
• Limitations of BCS as a Predictor of Drug Disposition
• Conclusion
• References
• Slide 36
• Slide 37

Solubility mgmL

DISS

GI

GI

S

TT

TC

rD

Dn2

3Diffusivity5x10-6 cm2s

Density12 mgcm3

Particle Radiusm

Residence time in GI 180 min

Time required forcomplete dissolution

Dissolution NumberA function of drug release from formulation

IVIVC expectations for immediate release products based on BCS

Class Solubility Permeability Absorption rate control

IVIVC expectations for Immediate release product

I High High Gastric emptying

IVIVC expected if dissolution rate is slower than gastric emptying rate otherwise limited or no correlations

II Low High Dissolution IVIVC expected if in vitro dissolution rate is similar to in vivo dissolution rate unless dose is very high

III High Low Permeability Absorption (permeability) is rate determining and limited or no IVIVC with dissolution

IV Low Low Case by case

Limited or no IVIVC is expected

High Solubility Low Solubility H

igh

Pe

rmea

bil

ity

Class 1 Abacavir Acetaminophen Acyclovirb AmilorideSI

Amitryptyline SI Antipyrine Atropine Buspironec Caffeine Captopril ChloroquineSI

Chlorpheniramine Cyclophosphamide Desipramine Diazepam Diltiazem SI Diphenhydramine Disopyramide Doxepin Doxycycline Enalapril Ephedrine Ergonovine Ethambutol Ethinyl Estradiol FluoxetineI

Glucose

ImipramineI Ketorolac Ketoprofen Labetolol LevodopaS Levofloxacin S LidocaineI Lomefloxacin Meperidine Metoprolol Metronidazole MidazolamSI Minocycline Misoprostol Nifedipine S Phenobarbital Phenylalanine Prednisolone PrimaquineS Promazine Propranolol I QuinidineSI Rosiglitazone Salicylic acid Theophylline Valproic acid Verapamil I Zidovudine

Class 2 Amiodarone I AtorvastatinS I AzithromycinS I

Carbamazepine SI Carvedilol Chlorpromazine I CisaprideS

Ciprofloxacin S Cyclosporine S I Danazol Dapsone Diclofenac Diflunisal Digoxin S Erythromycin SI Flurbiprofen Glipizide GlyburideSI Griseofulvin Ibuprofen Indinavir S

Indomethacin

Itraconazole SI Ketoconazole I LansoprazoleI Lovastatin SI Mebendazole Naproxen Nelfinavir SI Ofloxacin Oxaprozin Phenazopyridine PhenytoinS Piroxicam Raloxifene S Ritonavir SI Saquinavir SI Sirolimus S Spironolactone I Tacrolimus SI TalinololS

Tamoxifen I Terfenadine I Warfarin

High Solubility Low Solubility Lo

w P

erm

eabi

lity

Class 3 Acyclovir Amiloride SI Amoxicillin SI Atenolol Atropine Bisphosphonates Bidisomide Captopril Cefazolin Cetirizine Cimetidine S Ciprofloxacin S Cloxacillin Dicloxacillin S Erythromycin SI

Famotidine

Fexofenadine S Folinic acid Furosemide Ganciclovir Hydrochlorothiazide Lisinopril Metformin Methotrexate Nadolol Pravastatin S Penicillins Ranitidine S Tetracycline Trimethoprim S Valsartan Zalcitabine

Class 4 Amphotericin B Chlorthalidone Chlorothiazide Colistin Ciprofloxacin S Furosemide Hydrochlorothiazide Mebendazole Methotrexate Neomycin

Applications of BCS in oral drug delivery technology

Achieve a target release profile associated with a particular pharmacokinetic andor pharmacodynamic profile

Formulation approaches include both control of release rate and certain physicochemical properties of drugs like pH-solubility profile of drug

Class I - High Permeability High Solubility

Micronisation

Addition of surfactants

Formulation as emulsions and microemulsions systems

Use of complexing agents like cyclodextrins

Class II - High Permeability

Low Solubility

Require the technologies that address to fundamental limitations of absolute or regional permeability

Peptides and proteins constitute the part of class III and the technologies handling such materials are on rise now days

Class III - Low Permeability High Solubility

Class IV - Low Permeability Low Solubility

Major challenge for development of drug delivery system and the route of choice for administering such drugs is parenteral (solubility enhancers)

Fortunately extreme examples are the exception rather than the rule and are rarely developed and reach the market

Biowaiver A biowaiver is an exemption from

conducting human bioequivalence studies when the active ingredient(s) meet certain solubility and permeability criteria in vitro and when the dissolution profile of the dosage form meets the requirements for an immediate release dosage form

Waiver of In Vivo Bioequivalence Study based on

Pharmaceutical Dosage Form (Solutions)

Biopharmaceutics Classification System

Dose (Highest Strength should be tested)

BCS BIOWAIVER

Biowaiver for

Rapid and similar dissolution High solubility ampHigh permeability Wide therapeutic window Excipients used in dosage form used

previously in approved IR solid dosage forms

REQUEST FOR BIOWAIVERS

Data Supporting -

Rapid and Similar Dissolution

High Permeability

High Solubility

Limitations of BCS as a Predictor of Drug

DispositionΩ Permeability (90 absorption) is difficult to

determine and difficult to convince the regulatory agency

Ω There is little predictability for BCS classification drugs beyond Class 1 primarily due to the difficulty of determining and proving 90 absorption many drugs are misclassified (eg HIV protease inhibitors

as Class 4 compounds))

Conclusion BCS aims to provide a regulatory tool for

replacing certain BE studies by accurate in-vitro dissolution tests

This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in

drug molecules with a sufficiently high permeability solubility and dissolution

rate and that will automatically increase the importance of the BCS as

a regulatory tool over time

References Draft guidance for industry waiver of in vivo

bioavailability and bioequivalence studies for immediate release solid oral dosage forms containing certain active moieties active ingredients based on a biopharmaceutic classification system february 1999 CDERFDA

Amidon GL Lennernas H Shah VP Crison JRA A theoretical basis for a biopharmaceutic drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharm Res 12 413-420 (1995)

Guidance for industry immediate release solid oral dosage forms scale up and post approval changes november 1995 CDERFDA

Medicamento generico from website httpwwwAnvisaGo

Devane J Oral drug delivery technology addressing the solubility permeability paradigm pharm Technol 68-74 november 1998

Amidon G LLennernaumls H Shah V P And crisonj R A theoretical basis for a biopharmaceutics drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharmaceutical research 12 413-420 (1995)

Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA CDER 1997 1048603httpwwwfdagovcderguidance1713bp1pdf

Guidance for Industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System FDA CDER August 2000 httpwwwfdagovcderguidance3618fnlhtm

Thank you

• BIOPHARMACEUTICS CLASSIFICATION SYSTEM
• Contents
• Introduction
• Slide 4
• Slide 5
• Biopharmaceutics Classification System
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• DISSOLUTION DETERMINATION
• CLASS BOUNDARIES
• BCS Class Boundaries Objectives
• Slide 15
• BCS -Implications for drug development
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Applications of BCS in oral drug delivery technology
• Class II - High Permeability Low Solubility
• Slide 27
• Slide 28
• Biowaiver
• Waiver of In Vivo Bioequivalence Study based on
• BCS BIOWAIVER
• REQUEST FOR BIOWAIVERS
• Limitations of BCS as a Predictor of Drug Disposition
• Conclusion
• References
• Slide 36
• Slide 37

IVIVC expectations for immediate release products based on BCS

Class Solubility Permeability Absorption rate control

IVIVC expectations for Immediate release product

I High High Gastric emptying

IVIVC expected if dissolution rate is slower than gastric emptying rate otherwise limited or no correlations

II Low High Dissolution IVIVC expected if in vitro dissolution rate is similar to in vivo dissolution rate unless dose is very high

III High Low Permeability Absorption (permeability) is rate determining and limited or no IVIVC with dissolution

IV Low Low Case by case

Limited or no IVIVC is expected

High Solubility Low Solubility H

igh

Pe

rmea

bil

ity

Class 1 Abacavir Acetaminophen Acyclovirb AmilorideSI

Amitryptyline SI Antipyrine Atropine Buspironec Caffeine Captopril ChloroquineSI

Chlorpheniramine Cyclophosphamide Desipramine Diazepam Diltiazem SI Diphenhydramine Disopyramide Doxepin Doxycycline Enalapril Ephedrine Ergonovine Ethambutol Ethinyl Estradiol FluoxetineI

Glucose

ImipramineI Ketorolac Ketoprofen Labetolol LevodopaS Levofloxacin S LidocaineI Lomefloxacin Meperidine Metoprolol Metronidazole MidazolamSI Minocycline Misoprostol Nifedipine S Phenobarbital Phenylalanine Prednisolone PrimaquineS Promazine Propranolol I QuinidineSI Rosiglitazone Salicylic acid Theophylline Valproic acid Verapamil I Zidovudine

Class 2 Amiodarone I AtorvastatinS I AzithromycinS I

Carbamazepine SI Carvedilol Chlorpromazine I CisaprideS

Ciprofloxacin S Cyclosporine S I Danazol Dapsone Diclofenac Diflunisal Digoxin S Erythromycin SI Flurbiprofen Glipizide GlyburideSI Griseofulvin Ibuprofen Indinavir S

Indomethacin

Itraconazole SI Ketoconazole I LansoprazoleI Lovastatin SI Mebendazole Naproxen Nelfinavir SI Ofloxacin Oxaprozin Phenazopyridine PhenytoinS Piroxicam Raloxifene S Ritonavir SI Saquinavir SI Sirolimus S Spironolactone I Tacrolimus SI TalinololS

Tamoxifen I Terfenadine I Warfarin

High Solubility Low Solubility Lo

w P

erm

eabi

lity

Class 3 Acyclovir Amiloride SI Amoxicillin SI Atenolol Atropine Bisphosphonates Bidisomide Captopril Cefazolin Cetirizine Cimetidine S Ciprofloxacin S Cloxacillin Dicloxacillin S Erythromycin SI

Famotidine

Fexofenadine S Folinic acid Furosemide Ganciclovir Hydrochlorothiazide Lisinopril Metformin Methotrexate Nadolol Pravastatin S Penicillins Ranitidine S Tetracycline Trimethoprim S Valsartan Zalcitabine

Class 4 Amphotericin B Chlorthalidone Chlorothiazide Colistin Ciprofloxacin S Furosemide Hydrochlorothiazide Mebendazole Methotrexate Neomycin

Applications of BCS in oral drug delivery technology

Achieve a target release profile associated with a particular pharmacokinetic andor pharmacodynamic profile

Formulation approaches include both control of release rate and certain physicochemical properties of drugs like pH-solubility profile of drug

Class I - High Permeability High Solubility

Micronisation

Addition of surfactants

Formulation as emulsions and microemulsions systems

Use of complexing agents like cyclodextrins

Class II - High Permeability

Low Solubility

Require the technologies that address to fundamental limitations of absolute or regional permeability

Peptides and proteins constitute the part of class III and the technologies handling such materials are on rise now days

Class III - Low Permeability High Solubility

Class IV - Low Permeability Low Solubility

Major challenge for development of drug delivery system and the route of choice for administering such drugs is parenteral (solubility enhancers)

Fortunately extreme examples are the exception rather than the rule and are rarely developed and reach the market

Biowaiver A biowaiver is an exemption from

conducting human bioequivalence studies when the active ingredient(s) meet certain solubility and permeability criteria in vitro and when the dissolution profile of the dosage form meets the requirements for an immediate release dosage form

Waiver of In Vivo Bioequivalence Study based on

Pharmaceutical Dosage Form (Solutions)

Biopharmaceutics Classification System

Dose (Highest Strength should be tested)

BCS BIOWAIVER

Biowaiver for

Rapid and similar dissolution High solubility ampHigh permeability Wide therapeutic window Excipients used in dosage form used

previously in approved IR solid dosage forms

REQUEST FOR BIOWAIVERS

Data Supporting -

Rapid and Similar Dissolution

High Permeability

High Solubility

Limitations of BCS as a Predictor of Drug

DispositionΩ Permeability (90 absorption) is difficult to

determine and difficult to convince the regulatory agency

Ω There is little predictability for BCS classification drugs beyond Class 1 primarily due to the difficulty of determining and proving 90 absorption many drugs are misclassified (eg HIV protease inhibitors

as Class 4 compounds))

Conclusion BCS aims to provide a regulatory tool for

replacing certain BE studies by accurate in-vitro dissolution tests

This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in

drug molecules with a sufficiently high permeability solubility and dissolution

rate and that will automatically increase the importance of the BCS as

a regulatory tool over time

References Draft guidance for industry waiver of in vivo

bioavailability and bioequivalence studies for immediate release solid oral dosage forms containing certain active moieties active ingredients based on a biopharmaceutic classification system february 1999 CDERFDA

Amidon GL Lennernas H Shah VP Crison JRA A theoretical basis for a biopharmaceutic drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharm Res 12 413-420 (1995)

Guidance for industry immediate release solid oral dosage forms scale up and post approval changes november 1995 CDERFDA

Medicamento generico from website httpwwwAnvisaGo

Devane J Oral drug delivery technology addressing the solubility permeability paradigm pharm Technol 68-74 november 1998

Amidon G LLennernaumls H Shah V P And crisonj R A theoretical basis for a biopharmaceutics drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharmaceutical research 12 413-420 (1995)

Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA CDER 1997 1048603httpwwwfdagovcderguidance1713bp1pdf

Guidance for Industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System FDA CDER August 2000 httpwwwfdagovcderguidance3618fnlhtm

Thank you

• BIOPHARMACEUTICS CLASSIFICATION SYSTEM
• Contents
• Introduction
• Slide 4
• Slide 5
• Biopharmaceutics Classification System
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• DISSOLUTION DETERMINATION
• CLASS BOUNDARIES
• BCS Class Boundaries Objectives
• Slide 15
• BCS -Implications for drug development
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Applications of BCS in oral drug delivery technology
• Class II - High Permeability Low Solubility
• Slide 27
• Slide 28
• Biowaiver
• Waiver of In Vivo Bioequivalence Study based on
• BCS BIOWAIVER
• REQUEST FOR BIOWAIVERS
• Limitations of BCS as a Predictor of Drug Disposition
• Conclusion
• References
• Slide 36
• Slide 37

High Solubility Low Solubility H

igh

Pe

rmea

bil

ity

Class 1 Abacavir Acetaminophen Acyclovirb AmilorideSI

Amitryptyline SI Antipyrine Atropine Buspironec Caffeine Captopril ChloroquineSI

Chlorpheniramine Cyclophosphamide Desipramine Diazepam Diltiazem SI Diphenhydramine Disopyramide Doxepin Doxycycline Enalapril Ephedrine Ergonovine Ethambutol Ethinyl Estradiol FluoxetineI

Glucose

ImipramineI Ketorolac Ketoprofen Labetolol LevodopaS Levofloxacin S LidocaineI Lomefloxacin Meperidine Metoprolol Metronidazole MidazolamSI Minocycline Misoprostol Nifedipine S Phenobarbital Phenylalanine Prednisolone PrimaquineS Promazine Propranolol I QuinidineSI Rosiglitazone Salicylic acid Theophylline Valproic acid Verapamil I Zidovudine

Class 2 Amiodarone I AtorvastatinS I AzithromycinS I

Carbamazepine SI Carvedilol Chlorpromazine I CisaprideS

Ciprofloxacin S Cyclosporine S I Danazol Dapsone Diclofenac Diflunisal Digoxin S Erythromycin SI Flurbiprofen Glipizide GlyburideSI Griseofulvin Ibuprofen Indinavir S

Indomethacin

Itraconazole SI Ketoconazole I LansoprazoleI Lovastatin SI Mebendazole Naproxen Nelfinavir SI Ofloxacin Oxaprozin Phenazopyridine PhenytoinS Piroxicam Raloxifene S Ritonavir SI Saquinavir SI Sirolimus S Spironolactone I Tacrolimus SI TalinololS

Tamoxifen I Terfenadine I Warfarin

High Solubility Low Solubility Lo

w P

erm

eabi

lity

Class 3 Acyclovir Amiloride SI Amoxicillin SI Atenolol Atropine Bisphosphonates Bidisomide Captopril Cefazolin Cetirizine Cimetidine S Ciprofloxacin S Cloxacillin Dicloxacillin S Erythromycin SI

Famotidine

Fexofenadine S Folinic acid Furosemide Ganciclovir Hydrochlorothiazide Lisinopril Metformin Methotrexate Nadolol Pravastatin S Penicillins Ranitidine S Tetracycline Trimethoprim S Valsartan Zalcitabine

Class 4 Amphotericin B Chlorthalidone Chlorothiazide Colistin Ciprofloxacin S Furosemide Hydrochlorothiazide Mebendazole Methotrexate Neomycin

Applications of BCS in oral drug delivery technology

Achieve a target release profile associated with a particular pharmacokinetic andor pharmacodynamic profile

Formulation approaches include both control of release rate and certain physicochemical properties of drugs like pH-solubility profile of drug

Class I - High Permeability High Solubility

Micronisation

Addition of surfactants

Formulation as emulsions and microemulsions systems

Use of complexing agents like cyclodextrins

Class II - High Permeability

Low Solubility

Require the technologies that address to fundamental limitations of absolute or regional permeability

Peptides and proteins constitute the part of class III and the technologies handling such materials are on rise now days

Class III - Low Permeability High Solubility

Class IV - Low Permeability Low Solubility

Major challenge for development of drug delivery system and the route of choice for administering such drugs is parenteral (solubility enhancers)

Fortunately extreme examples are the exception rather than the rule and are rarely developed and reach the market

Biowaiver A biowaiver is an exemption from

conducting human bioequivalence studies when the active ingredient(s) meet certain solubility and permeability criteria in vitro and when the dissolution profile of the dosage form meets the requirements for an immediate release dosage form

Waiver of In Vivo Bioequivalence Study based on

Pharmaceutical Dosage Form (Solutions)

Biopharmaceutics Classification System

Dose (Highest Strength should be tested)

BCS BIOWAIVER

Biowaiver for

Rapid and similar dissolution High solubility ampHigh permeability Wide therapeutic window Excipients used in dosage form used

previously in approved IR solid dosage forms

REQUEST FOR BIOWAIVERS

Data Supporting -

Rapid and Similar Dissolution

High Permeability

High Solubility

Limitations of BCS as a Predictor of Drug

DispositionΩ Permeability (90 absorption) is difficult to

determine and difficult to convince the regulatory agency

Ω There is little predictability for BCS classification drugs beyond Class 1 primarily due to the difficulty of determining and proving 90 absorption many drugs are misclassified (eg HIV protease inhibitors

as Class 4 compounds))

Conclusion BCS aims to provide a regulatory tool for

replacing certain BE studies by accurate in-vitro dissolution tests

This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in

drug molecules with a sufficiently high permeability solubility and dissolution

rate and that will automatically increase the importance of the BCS as

a regulatory tool over time

References Draft guidance for industry waiver of in vivo

bioavailability and bioequivalence studies for immediate release solid oral dosage forms containing certain active moieties active ingredients based on a biopharmaceutic classification system february 1999 CDERFDA

Amidon GL Lennernas H Shah VP Crison JRA A theoretical basis for a biopharmaceutic drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharm Res 12 413-420 (1995)

Guidance for industry immediate release solid oral dosage forms scale up and post approval changes november 1995 CDERFDA

Medicamento generico from website httpwwwAnvisaGo

Devane J Oral drug delivery technology addressing the solubility permeability paradigm pharm Technol 68-74 november 1998

Amidon G LLennernaumls H Shah V P And crisonj R A theoretical basis for a biopharmaceutics drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharmaceutical research 12 413-420 (1995)

Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA CDER 1997 1048603httpwwwfdagovcderguidance1713bp1pdf

Guidance for Industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System FDA CDER August 2000 httpwwwfdagovcderguidance3618fnlhtm

Thank you

• BIOPHARMACEUTICS CLASSIFICATION SYSTEM
• Contents
• Introduction
• Slide 4
• Slide 5
• Biopharmaceutics Classification System
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• DISSOLUTION DETERMINATION
• CLASS BOUNDARIES
• BCS Class Boundaries Objectives
• Slide 15
• BCS -Implications for drug development
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Applications of BCS in oral drug delivery technology
• Class II - High Permeability Low Solubility
• Slide 27
• Slide 28
• Biowaiver
• Waiver of In Vivo Bioequivalence Study based on
• BCS BIOWAIVER
• REQUEST FOR BIOWAIVERS
• Limitations of BCS as a Predictor of Drug Disposition
• Conclusion
• References
• Slide 36
• Slide 37

High Solubility Low Solubility Lo

w P

erm

eabi

lity

Class 3 Acyclovir Amiloride SI Amoxicillin SI Atenolol Atropine Bisphosphonates Bidisomide Captopril Cefazolin Cetirizine Cimetidine S Ciprofloxacin S Cloxacillin Dicloxacillin S Erythromycin SI

Famotidine

Fexofenadine S Folinic acid Furosemide Ganciclovir Hydrochlorothiazide Lisinopril Metformin Methotrexate Nadolol Pravastatin S Penicillins Ranitidine S Tetracycline Trimethoprim S Valsartan Zalcitabine

Class 4 Amphotericin B Chlorthalidone Chlorothiazide Colistin Ciprofloxacin S Furosemide Hydrochlorothiazide Mebendazole Methotrexate Neomycin

Applications of BCS in oral drug delivery technology

Achieve a target release profile associated with a particular pharmacokinetic andor pharmacodynamic profile

Formulation approaches include both control of release rate and certain physicochemical properties of drugs like pH-solubility profile of drug

Class I - High Permeability High Solubility

Micronisation

Addition of surfactants

Formulation as emulsions and microemulsions systems

Use of complexing agents like cyclodextrins

Class II - High Permeability

Low Solubility

Require the technologies that address to fundamental limitations of absolute or regional permeability

Peptides and proteins constitute the part of class III and the technologies handling such materials are on rise now days

Class III - Low Permeability High Solubility

Class IV - Low Permeability Low Solubility

Major challenge for development of drug delivery system and the route of choice for administering such drugs is parenteral (solubility enhancers)

Fortunately extreme examples are the exception rather than the rule and are rarely developed and reach the market

Biowaiver A biowaiver is an exemption from

conducting human bioequivalence studies when the active ingredient(s) meet certain solubility and permeability criteria in vitro and when the dissolution profile of the dosage form meets the requirements for an immediate release dosage form

Waiver of In Vivo Bioequivalence Study based on

Pharmaceutical Dosage Form (Solutions)

Biopharmaceutics Classification System

Dose (Highest Strength should be tested)

BCS BIOWAIVER

Biowaiver for

Rapid and similar dissolution High solubility ampHigh permeability Wide therapeutic window Excipients used in dosage form used

previously in approved IR solid dosage forms

REQUEST FOR BIOWAIVERS

Data Supporting -

Rapid and Similar Dissolution

High Permeability

High Solubility

Limitations of BCS as a Predictor of Drug

DispositionΩ Permeability (90 absorption) is difficult to

determine and difficult to convince the regulatory agency

Ω There is little predictability for BCS classification drugs beyond Class 1 primarily due to the difficulty of determining and proving 90 absorption many drugs are misclassified (eg HIV protease inhibitors

as Class 4 compounds))

Conclusion BCS aims to provide a regulatory tool for

replacing certain BE studies by accurate in-vitro dissolution tests

This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in

drug molecules with a sufficiently high permeability solubility and dissolution

rate and that will automatically increase the importance of the BCS as

a regulatory tool over time

References Draft guidance for industry waiver of in vivo

bioavailability and bioequivalence studies for immediate release solid oral dosage forms containing certain active moieties active ingredients based on a biopharmaceutic classification system february 1999 CDERFDA

Amidon GL Lennernas H Shah VP Crison JRA A theoretical basis for a biopharmaceutic drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharm Res 12 413-420 (1995)

Guidance for industry immediate release solid oral dosage forms scale up and post approval changes november 1995 CDERFDA

Medicamento generico from website httpwwwAnvisaGo

Devane J Oral drug delivery technology addressing the solubility permeability paradigm pharm Technol 68-74 november 1998

Amidon G LLennernaumls H Shah V P And crisonj R A theoretical basis for a biopharmaceutics drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharmaceutical research 12 413-420 (1995)

Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA CDER 1997 1048603httpwwwfdagovcderguidance1713bp1pdf

Guidance for Industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System FDA CDER August 2000 httpwwwfdagovcderguidance3618fnlhtm

Thank you

• BIOPHARMACEUTICS CLASSIFICATION SYSTEM
• Contents
• Introduction
• Slide 4
• Slide 5
• Biopharmaceutics Classification System
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• DISSOLUTION DETERMINATION
• CLASS BOUNDARIES
• BCS Class Boundaries Objectives
• Slide 15
• BCS -Implications for drug development
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Applications of BCS in oral drug delivery technology
• Class II - High Permeability Low Solubility
• Slide 27
• Slide 28
• Biowaiver
• Waiver of In Vivo Bioequivalence Study based on
• BCS BIOWAIVER
• REQUEST FOR BIOWAIVERS
• Limitations of BCS as a Predictor of Drug Disposition
• Conclusion
• References
• Slide 36
• Slide 37

Applications of BCS in oral drug delivery technology

Achieve a target release profile associated with a particular pharmacokinetic andor pharmacodynamic profile

Formulation approaches include both control of release rate and certain physicochemical properties of drugs like pH-solubility profile of drug

Class I - High Permeability High Solubility

Micronisation

Addition of surfactants

Formulation as emulsions and microemulsions systems

Use of complexing agents like cyclodextrins

Class II - High Permeability

Low Solubility

Require the technologies that address to fundamental limitations of absolute or regional permeability

Peptides and proteins constitute the part of class III and the technologies handling such materials are on rise now days

Class III - Low Permeability High Solubility

Class IV - Low Permeability Low Solubility

Major challenge for development of drug delivery system and the route of choice for administering such drugs is parenteral (solubility enhancers)

Fortunately extreme examples are the exception rather than the rule and are rarely developed and reach the market

Biowaiver A biowaiver is an exemption from

conducting human bioequivalence studies when the active ingredient(s) meet certain solubility and permeability criteria in vitro and when the dissolution profile of the dosage form meets the requirements for an immediate release dosage form

Waiver of In Vivo Bioequivalence Study based on

Pharmaceutical Dosage Form (Solutions)

Biopharmaceutics Classification System

Dose (Highest Strength should be tested)

BCS BIOWAIVER

Biowaiver for

Rapid and similar dissolution High solubility ampHigh permeability Wide therapeutic window Excipients used in dosage form used

previously in approved IR solid dosage forms

REQUEST FOR BIOWAIVERS

Data Supporting -

Rapid and Similar Dissolution

High Permeability

High Solubility

Limitations of BCS as a Predictor of Drug

DispositionΩ Permeability (90 absorption) is difficult to

determine and difficult to convince the regulatory agency

Ω There is little predictability for BCS classification drugs beyond Class 1 primarily due to the difficulty of determining and proving 90 absorption many drugs are misclassified (eg HIV protease inhibitors

as Class 4 compounds))

Conclusion BCS aims to provide a regulatory tool for

replacing certain BE studies by accurate in-vitro dissolution tests

This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in

drug molecules with a sufficiently high permeability solubility and dissolution

rate and that will automatically increase the importance of the BCS as

a regulatory tool over time

References Draft guidance for industry waiver of in vivo

bioavailability and bioequivalence studies for immediate release solid oral dosage forms containing certain active moieties active ingredients based on a biopharmaceutic classification system february 1999 CDERFDA

Amidon GL Lennernas H Shah VP Crison JRA A theoretical basis for a biopharmaceutic drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharm Res 12 413-420 (1995)

Guidance for industry immediate release solid oral dosage forms scale up and post approval changes november 1995 CDERFDA

Medicamento generico from website httpwwwAnvisaGo

Devane J Oral drug delivery technology addressing the solubility permeability paradigm pharm Technol 68-74 november 1998

Amidon G LLennernaumls H Shah V P And crisonj R A theoretical basis for a biopharmaceutics drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharmaceutical research 12 413-420 (1995)

Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA CDER 1997 1048603httpwwwfdagovcderguidance1713bp1pdf

Guidance for Industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System FDA CDER August 2000 httpwwwfdagovcderguidance3618fnlhtm

Thank you

• BIOPHARMACEUTICS CLASSIFICATION SYSTEM
• Contents
• Introduction
• Slide 4
• Slide 5
• Biopharmaceutics Classification System
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• DISSOLUTION DETERMINATION
• CLASS BOUNDARIES
• BCS Class Boundaries Objectives
• Slide 15
• BCS -Implications for drug development
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Applications of BCS in oral drug delivery technology
• Class II - High Permeability Low Solubility
• Slide 27
• Slide 28
• Biowaiver
• Waiver of In Vivo Bioequivalence Study based on
• BCS BIOWAIVER
• REQUEST FOR BIOWAIVERS
• Limitations of BCS as a Predictor of Drug Disposition
• Conclusion
• References
• Slide 36
• Slide 37

Micronisation

Addition of surfactants

Formulation as emulsions and microemulsions systems

Use of complexing agents like cyclodextrins

Class II - High Permeability

Low Solubility

Require the technologies that address to fundamental limitations of absolute or regional permeability

Peptides and proteins constitute the part of class III and the technologies handling such materials are on rise now days

Class III - Low Permeability High Solubility

Class IV - Low Permeability Low Solubility

Major challenge for development of drug delivery system and the route of choice for administering such drugs is parenteral (solubility enhancers)

Fortunately extreme examples are the exception rather than the rule and are rarely developed and reach the market

Biowaiver A biowaiver is an exemption from

conducting human bioequivalence studies when the active ingredient(s) meet certain solubility and permeability criteria in vitro and when the dissolution profile of the dosage form meets the requirements for an immediate release dosage form

Waiver of In Vivo Bioequivalence Study based on

Pharmaceutical Dosage Form (Solutions)

Biopharmaceutics Classification System

Dose (Highest Strength should be tested)

BCS BIOWAIVER

Biowaiver for

Rapid and similar dissolution High solubility ampHigh permeability Wide therapeutic window Excipients used in dosage form used

previously in approved IR solid dosage forms

REQUEST FOR BIOWAIVERS

Data Supporting -

Rapid and Similar Dissolution

High Permeability

High Solubility

Limitations of BCS as a Predictor of Drug

DispositionΩ Permeability (90 absorption) is difficult to

determine and difficult to convince the regulatory agency

Ω There is little predictability for BCS classification drugs beyond Class 1 primarily due to the difficulty of determining and proving 90 absorption many drugs are misclassified (eg HIV protease inhibitors

as Class 4 compounds))

Conclusion BCS aims to provide a regulatory tool for

replacing certain BE studies by accurate in-vitro dissolution tests

This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in

drug molecules with a sufficiently high permeability solubility and dissolution

rate and that will automatically increase the importance of the BCS as

a regulatory tool over time

References Draft guidance for industry waiver of in vivo

bioavailability and bioequivalence studies for immediate release solid oral dosage forms containing certain active moieties active ingredients based on a biopharmaceutic classification system february 1999 CDERFDA

Amidon GL Lennernas H Shah VP Crison JRA A theoretical basis for a biopharmaceutic drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharm Res 12 413-420 (1995)

Guidance for industry immediate release solid oral dosage forms scale up and post approval changes november 1995 CDERFDA

Medicamento generico from website httpwwwAnvisaGo

Devane J Oral drug delivery technology addressing the solubility permeability paradigm pharm Technol 68-74 november 1998

Amidon G LLennernaumls H Shah V P And crisonj R A theoretical basis for a biopharmaceutics drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharmaceutical research 12 413-420 (1995)

Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA CDER 1997 1048603httpwwwfdagovcderguidance1713bp1pdf

Guidance for Industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System FDA CDER August 2000 httpwwwfdagovcderguidance3618fnlhtm

Thank you

• BIOPHARMACEUTICS CLASSIFICATION SYSTEM
• Contents
• Introduction
• Slide 4
• Slide 5
• Biopharmaceutics Classification System
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• DISSOLUTION DETERMINATION
• CLASS BOUNDARIES
• BCS Class Boundaries Objectives
• Slide 15
• BCS -Implications for drug development
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Applications of BCS in oral drug delivery technology
• Class II - High Permeability Low Solubility
• Slide 27
• Slide 28
• Biowaiver
• Waiver of In Vivo Bioequivalence Study based on
• BCS BIOWAIVER
• REQUEST FOR BIOWAIVERS
• Limitations of BCS as a Predictor of Drug Disposition
• Conclusion
• References
• Slide 36
• Slide 37

Require the technologies that address to fundamental limitations of absolute or regional permeability

Peptides and proteins constitute the part of class III and the technologies handling such materials are on rise now days

Class III - Low Permeability High Solubility

Class IV - Low Permeability Low Solubility

Major challenge for development of drug delivery system and the route of choice for administering such drugs is parenteral (solubility enhancers)

Fortunately extreme examples are the exception rather than the rule and are rarely developed and reach the market

Biowaiver A biowaiver is an exemption from

conducting human bioequivalence studies when the active ingredient(s) meet certain solubility and permeability criteria in vitro and when the dissolution profile of the dosage form meets the requirements for an immediate release dosage form

Waiver of In Vivo Bioequivalence Study based on

Pharmaceutical Dosage Form (Solutions)

Biopharmaceutics Classification System

Dose (Highest Strength should be tested)

BCS BIOWAIVER

Biowaiver for

Rapid and similar dissolution High solubility ampHigh permeability Wide therapeutic window Excipients used in dosage form used

previously in approved IR solid dosage forms

REQUEST FOR BIOWAIVERS

Data Supporting -

Rapid and Similar Dissolution

High Permeability

High Solubility

Limitations of BCS as a Predictor of Drug

DispositionΩ Permeability (90 absorption) is difficult to

determine and difficult to convince the regulatory agency

Ω There is little predictability for BCS classification drugs beyond Class 1 primarily due to the difficulty of determining and proving 90 absorption many drugs are misclassified (eg HIV protease inhibitors

as Class 4 compounds))

Conclusion BCS aims to provide a regulatory tool for

replacing certain BE studies by accurate in-vitro dissolution tests

This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in

drug molecules with a sufficiently high permeability solubility and dissolution

rate and that will automatically increase the importance of the BCS as

a regulatory tool over time

References Draft guidance for industry waiver of in vivo

bioavailability and bioequivalence studies for immediate release solid oral dosage forms containing certain active moieties active ingredients based on a biopharmaceutic classification system february 1999 CDERFDA

Amidon GL Lennernas H Shah VP Crison JRA A theoretical basis for a biopharmaceutic drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharm Res 12 413-420 (1995)

Guidance for industry immediate release solid oral dosage forms scale up and post approval changes november 1995 CDERFDA

Medicamento generico from website httpwwwAnvisaGo

Devane J Oral drug delivery technology addressing the solubility permeability paradigm pharm Technol 68-74 november 1998

Amidon G LLennernaumls H Shah V P And crisonj R A theoretical basis for a biopharmaceutics drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharmaceutical research 12 413-420 (1995)

Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA CDER 1997 1048603httpwwwfdagovcderguidance1713bp1pdf

Guidance for Industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System FDA CDER August 2000 httpwwwfdagovcderguidance3618fnlhtm

Thank you

• BIOPHARMACEUTICS CLASSIFICATION SYSTEM
• Contents
• Introduction
• Slide 4
• Slide 5
• Biopharmaceutics Classification System
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• DISSOLUTION DETERMINATION
• CLASS BOUNDARIES
• BCS Class Boundaries Objectives
• Slide 15
• BCS -Implications for drug development
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Applications of BCS in oral drug delivery technology
• Class II - High Permeability Low Solubility
• Slide 27
• Slide 28
• Biowaiver
• Waiver of In Vivo Bioequivalence Study based on
• BCS BIOWAIVER
• REQUEST FOR BIOWAIVERS
• Limitations of BCS as a Predictor of Drug Disposition
• Conclusion
• References
• Slide 36
• Slide 37

Class IV - Low Permeability Low Solubility

Major challenge for development of drug delivery system and the route of choice for administering such drugs is parenteral (solubility enhancers)

Fortunately extreme examples are the exception rather than the rule and are rarely developed and reach the market

Biowaiver A biowaiver is an exemption from

conducting human bioequivalence studies when the active ingredient(s) meet certain solubility and permeability criteria in vitro and when the dissolution profile of the dosage form meets the requirements for an immediate release dosage form

Waiver of In Vivo Bioequivalence Study based on

Pharmaceutical Dosage Form (Solutions)

Biopharmaceutics Classification System

Dose (Highest Strength should be tested)

BCS BIOWAIVER

Biowaiver for

Rapid and similar dissolution High solubility ampHigh permeability Wide therapeutic window Excipients used in dosage form used

previously in approved IR solid dosage forms

REQUEST FOR BIOWAIVERS

Data Supporting -

Rapid and Similar Dissolution

High Permeability

High Solubility

Limitations of BCS as a Predictor of Drug

DispositionΩ Permeability (90 absorption) is difficult to

determine and difficult to convince the regulatory agency

Ω There is little predictability for BCS classification drugs beyond Class 1 primarily due to the difficulty of determining and proving 90 absorption many drugs are misclassified (eg HIV protease inhibitors

as Class 4 compounds))

Conclusion BCS aims to provide a regulatory tool for

replacing certain BE studies by accurate in-vitro dissolution tests

This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in

drug molecules with a sufficiently high permeability solubility and dissolution

rate and that will automatically increase the importance of the BCS as

a regulatory tool over time

References Draft guidance for industry waiver of in vivo

bioavailability and bioequivalence studies for immediate release solid oral dosage forms containing certain active moieties active ingredients based on a biopharmaceutic classification system february 1999 CDERFDA

Amidon GL Lennernas H Shah VP Crison JRA A theoretical basis for a biopharmaceutic drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharm Res 12 413-420 (1995)

Guidance for industry immediate release solid oral dosage forms scale up and post approval changes november 1995 CDERFDA

Medicamento generico from website httpwwwAnvisaGo

Devane J Oral drug delivery technology addressing the solubility permeability paradigm pharm Technol 68-74 november 1998

Amidon G LLennernaumls H Shah V P And crisonj R A theoretical basis for a biopharmaceutics drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharmaceutical research 12 413-420 (1995)

Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA CDER 1997 1048603httpwwwfdagovcderguidance1713bp1pdf

Guidance for Industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System FDA CDER August 2000 httpwwwfdagovcderguidance3618fnlhtm

Thank you

• BIOPHARMACEUTICS CLASSIFICATION SYSTEM
• Contents
• Introduction
• Slide 4
• Slide 5
• Biopharmaceutics Classification System
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• DISSOLUTION DETERMINATION
• CLASS BOUNDARIES
• BCS Class Boundaries Objectives
• Slide 15
• BCS -Implications for drug development
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Applications of BCS in oral drug delivery technology
• Class II - High Permeability Low Solubility
• Slide 27
• Slide 28
• Biowaiver
• Waiver of In Vivo Bioequivalence Study based on
• BCS BIOWAIVER
• REQUEST FOR BIOWAIVERS
• Limitations of BCS as a Predictor of Drug Disposition
• Conclusion
• References
• Slide 36
• Slide 37

Biowaiver A biowaiver is an exemption from

conducting human bioequivalence studies when the active ingredient(s) meet certain solubility and permeability criteria in vitro and when the dissolution profile of the dosage form meets the requirements for an immediate release dosage form

Waiver of In Vivo Bioequivalence Study based on

Pharmaceutical Dosage Form (Solutions)

Biopharmaceutics Classification System

Dose (Highest Strength should be tested)

BCS BIOWAIVER

Biowaiver for

Rapid and similar dissolution High solubility ampHigh permeability Wide therapeutic window Excipients used in dosage form used

previously in approved IR solid dosage forms

REQUEST FOR BIOWAIVERS

Data Supporting -

Rapid and Similar Dissolution

High Permeability

High Solubility

Limitations of BCS as a Predictor of Drug

DispositionΩ Permeability (90 absorption) is difficult to

determine and difficult to convince the regulatory agency

Ω There is little predictability for BCS classification drugs beyond Class 1 primarily due to the difficulty of determining and proving 90 absorption many drugs are misclassified (eg HIV protease inhibitors

as Class 4 compounds))

Conclusion BCS aims to provide a regulatory tool for

replacing certain BE studies by accurate in-vitro dissolution tests

This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in

drug molecules with a sufficiently high permeability solubility and dissolution

rate and that will automatically increase the importance of the BCS as

a regulatory tool over time

References Draft guidance for industry waiver of in vivo

bioavailability and bioequivalence studies for immediate release solid oral dosage forms containing certain active moieties active ingredients based on a biopharmaceutic classification system february 1999 CDERFDA

Amidon GL Lennernas H Shah VP Crison JRA A theoretical basis for a biopharmaceutic drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharm Res 12 413-420 (1995)

Guidance for industry immediate release solid oral dosage forms scale up and post approval changes november 1995 CDERFDA

Medicamento generico from website httpwwwAnvisaGo

Devane J Oral drug delivery technology addressing the solubility permeability paradigm pharm Technol 68-74 november 1998

Amidon G LLennernaumls H Shah V P And crisonj R A theoretical basis for a biopharmaceutics drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharmaceutical research 12 413-420 (1995)

Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA CDER 1997 1048603httpwwwfdagovcderguidance1713bp1pdf

Guidance for Industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System FDA CDER August 2000 httpwwwfdagovcderguidance3618fnlhtm

Thank you

• BIOPHARMACEUTICS CLASSIFICATION SYSTEM
• Contents
• Introduction
• Slide 4
• Slide 5
• Biopharmaceutics Classification System
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• DISSOLUTION DETERMINATION
• CLASS BOUNDARIES
• BCS Class Boundaries Objectives
• Slide 15
• BCS -Implications for drug development
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Applications of BCS in oral drug delivery technology
• Class II - High Permeability Low Solubility
• Slide 27
• Slide 28
• Biowaiver
• Waiver of In Vivo Bioequivalence Study based on
• BCS BIOWAIVER
• REQUEST FOR BIOWAIVERS
• Limitations of BCS as a Predictor of Drug Disposition
• Conclusion
• References
• Slide 36
• Slide 37

Waiver of In Vivo Bioequivalence Study based on

Pharmaceutical Dosage Form (Solutions)

Biopharmaceutics Classification System

Dose (Highest Strength should be tested)

BCS BIOWAIVER

Biowaiver for

Rapid and similar dissolution High solubility ampHigh permeability Wide therapeutic window Excipients used in dosage form used

previously in approved IR solid dosage forms

REQUEST FOR BIOWAIVERS

Data Supporting -

Rapid and Similar Dissolution

High Permeability

High Solubility

Limitations of BCS as a Predictor of Drug

DispositionΩ Permeability (90 absorption) is difficult to

determine and difficult to convince the regulatory agency

Ω There is little predictability for BCS classification drugs beyond Class 1 primarily due to the difficulty of determining and proving 90 absorption many drugs are misclassified (eg HIV protease inhibitors

as Class 4 compounds))

Conclusion BCS aims to provide a regulatory tool for

replacing certain BE studies by accurate in-vitro dissolution tests

This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in

drug molecules with a sufficiently high permeability solubility and dissolution

rate and that will automatically increase the importance of the BCS as

a regulatory tool over time

References Draft guidance for industry waiver of in vivo

bioavailability and bioequivalence studies for immediate release solid oral dosage forms containing certain active moieties active ingredients based on a biopharmaceutic classification system february 1999 CDERFDA

Amidon GL Lennernas H Shah VP Crison JRA A theoretical basis for a biopharmaceutic drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharm Res 12 413-420 (1995)

Guidance for industry immediate release solid oral dosage forms scale up and post approval changes november 1995 CDERFDA

Medicamento generico from website httpwwwAnvisaGo

Devane J Oral drug delivery technology addressing the solubility permeability paradigm pharm Technol 68-74 november 1998

Amidon G LLennernaumls H Shah V P And crisonj R A theoretical basis for a biopharmaceutics drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharmaceutical research 12 413-420 (1995)

Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA CDER 1997 1048603httpwwwfdagovcderguidance1713bp1pdf

Guidance for Industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System FDA CDER August 2000 httpwwwfdagovcderguidance3618fnlhtm

Thank you

• BIOPHARMACEUTICS CLASSIFICATION SYSTEM
• Contents
• Introduction
• Slide 4
• Slide 5
• Biopharmaceutics Classification System
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• DISSOLUTION DETERMINATION
• CLASS BOUNDARIES
• BCS Class Boundaries Objectives
• Slide 15
• BCS -Implications for drug development
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Applications of BCS in oral drug delivery technology
• Class II - High Permeability Low Solubility
• Slide 27
• Slide 28
• Biowaiver
• Waiver of In Vivo Bioequivalence Study based on
• BCS BIOWAIVER
• REQUEST FOR BIOWAIVERS
• Limitations of BCS as a Predictor of Drug Disposition
• Conclusion
• References
• Slide 36
• Slide 37

BCS BIOWAIVER

Biowaiver for

Rapid and similar dissolution High solubility ampHigh permeability Wide therapeutic window Excipients used in dosage form used

previously in approved IR solid dosage forms

REQUEST FOR BIOWAIVERS

Data Supporting -

Rapid and Similar Dissolution

High Permeability

High Solubility

Limitations of BCS as a Predictor of Drug

DispositionΩ Permeability (90 absorption) is difficult to

determine and difficult to convince the regulatory agency

Ω There is little predictability for BCS classification drugs beyond Class 1 primarily due to the difficulty of determining and proving 90 absorption many drugs are misclassified (eg HIV protease inhibitors

as Class 4 compounds))

Conclusion BCS aims to provide a regulatory tool for

replacing certain BE studies by accurate in-vitro dissolution tests

This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in

drug molecules with a sufficiently high permeability solubility and dissolution

rate and that will automatically increase the importance of the BCS as

a regulatory tool over time

References Draft guidance for industry waiver of in vivo

bioavailability and bioequivalence studies for immediate release solid oral dosage forms containing certain active moieties active ingredients based on a biopharmaceutic classification system february 1999 CDERFDA

Amidon GL Lennernas H Shah VP Crison JRA A theoretical basis for a biopharmaceutic drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharm Res 12 413-420 (1995)

Guidance for industry immediate release solid oral dosage forms scale up and post approval changes november 1995 CDERFDA

Medicamento generico from website httpwwwAnvisaGo

Devane J Oral drug delivery technology addressing the solubility permeability paradigm pharm Technol 68-74 november 1998

Amidon G LLennernaumls H Shah V P And crisonj R A theoretical basis for a biopharmaceutics drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharmaceutical research 12 413-420 (1995)

Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA CDER 1997 1048603httpwwwfdagovcderguidance1713bp1pdf

Guidance for Industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System FDA CDER August 2000 httpwwwfdagovcderguidance3618fnlhtm

Thank you

• BIOPHARMACEUTICS CLASSIFICATION SYSTEM
• Contents
• Introduction
• Slide 4
• Slide 5
• Biopharmaceutics Classification System
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• DISSOLUTION DETERMINATION
• CLASS BOUNDARIES
• BCS Class Boundaries Objectives
• Slide 15
• BCS -Implications for drug development
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Applications of BCS in oral drug delivery technology
• Class II - High Permeability Low Solubility
• Slide 27
• Slide 28
• Biowaiver
• Waiver of In Vivo Bioequivalence Study based on
• BCS BIOWAIVER
• REQUEST FOR BIOWAIVERS
• Limitations of BCS as a Predictor of Drug Disposition
• Conclusion
• References
• Slide 36
• Slide 37

REQUEST FOR BIOWAIVERS

Data Supporting -

Rapid and Similar Dissolution

High Permeability

High Solubility

Limitations of BCS as a Predictor of Drug

DispositionΩ Permeability (90 absorption) is difficult to

determine and difficult to convince the regulatory agency

Ω There is little predictability for BCS classification drugs beyond Class 1 primarily due to the difficulty of determining and proving 90 absorption many drugs are misclassified (eg HIV protease inhibitors

as Class 4 compounds))

Conclusion BCS aims to provide a regulatory tool for

replacing certain BE studies by accurate in-vitro dissolution tests

This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in

drug molecules with a sufficiently high permeability solubility and dissolution

rate and that will automatically increase the importance of the BCS as

a regulatory tool over time

References Draft guidance for industry waiver of in vivo

bioavailability and bioequivalence studies for immediate release solid oral dosage forms containing certain active moieties active ingredients based on a biopharmaceutic classification system february 1999 CDERFDA

Amidon GL Lennernas H Shah VP Crison JRA A theoretical basis for a biopharmaceutic drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharm Res 12 413-420 (1995)

Guidance for industry immediate release solid oral dosage forms scale up and post approval changes november 1995 CDERFDA

Medicamento generico from website httpwwwAnvisaGo

Devane J Oral drug delivery technology addressing the solubility permeability paradigm pharm Technol 68-74 november 1998

Amidon G LLennernaumls H Shah V P And crisonj R A theoretical basis for a biopharmaceutics drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharmaceutical research 12 413-420 (1995)

Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA CDER 1997 1048603httpwwwfdagovcderguidance1713bp1pdf

Guidance for Industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System FDA CDER August 2000 httpwwwfdagovcderguidance3618fnlhtm

Thank you

• BIOPHARMACEUTICS CLASSIFICATION SYSTEM
• Contents
• Introduction
• Slide 4
• Slide 5
• Biopharmaceutics Classification System
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• DISSOLUTION DETERMINATION
• CLASS BOUNDARIES
• BCS Class Boundaries Objectives
• Slide 15
• BCS -Implications for drug development
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Applications of BCS in oral drug delivery technology
• Class II - High Permeability Low Solubility
• Slide 27
• Slide 28
• Biowaiver
• Waiver of In Vivo Bioequivalence Study based on
• BCS BIOWAIVER
• REQUEST FOR BIOWAIVERS
• Limitations of BCS as a Predictor of Drug Disposition
• Conclusion
• References
• Slide 36
• Slide 37

Limitations of BCS as a Predictor of Drug

DispositionΩ Permeability (90 absorption) is difficult to

determine and difficult to convince the regulatory agency

Ω There is little predictability for BCS classification drugs beyond Class 1 primarily due to the difficulty of determining and proving 90 absorption many drugs are misclassified (eg HIV protease inhibitors

as Class 4 compounds))

Conclusion BCS aims to provide a regulatory tool for

replacing certain BE studies by accurate in-vitro dissolution tests

This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in

drug molecules with a sufficiently high permeability solubility and dissolution

rate and that will automatically increase the importance of the BCS as

a regulatory tool over time

References Draft guidance for industry waiver of in vivo

bioavailability and bioequivalence studies for immediate release solid oral dosage forms containing certain active moieties active ingredients based on a biopharmaceutic classification system february 1999 CDERFDA

Amidon GL Lennernas H Shah VP Crison JRA A theoretical basis for a biopharmaceutic drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharm Res 12 413-420 (1995)

Guidance for industry immediate release solid oral dosage forms scale up and post approval changes november 1995 CDERFDA

Medicamento generico from website httpwwwAnvisaGo

Devane J Oral drug delivery technology addressing the solubility permeability paradigm pharm Technol 68-74 november 1998

Amidon G LLennernaumls H Shah V P And crisonj R A theoretical basis for a biopharmaceutics drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharmaceutical research 12 413-420 (1995)

Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA CDER 1997 1048603httpwwwfdagovcderguidance1713bp1pdf

Guidance for Industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System FDA CDER August 2000 httpwwwfdagovcderguidance3618fnlhtm

Thank you

• BIOPHARMACEUTICS CLASSIFICATION SYSTEM
• Contents
• Introduction
• Slide 4
• Slide 5
• Biopharmaceutics Classification System
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• DISSOLUTION DETERMINATION
• CLASS BOUNDARIES
• BCS Class Boundaries Objectives
• Slide 15
• BCS -Implications for drug development
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Applications of BCS in oral drug delivery technology
• Class II - High Permeability Low Solubility
• Slide 27
• Slide 28
• Biowaiver
• Waiver of In Vivo Bioequivalence Study based on
• BCS BIOWAIVER
• REQUEST FOR BIOWAIVERS
• Limitations of BCS as a Predictor of Drug Disposition
• Conclusion
• References
• Slide 36
• Slide 37

Conclusion BCS aims to provide a regulatory tool for

replacing certain BE studies by accurate in-vitro dissolution tests

This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in

drug molecules with a sufficiently high permeability solubility and dissolution

rate and that will automatically increase the importance of the BCS as

a regulatory tool over time

References Draft guidance for industry waiver of in vivo

bioavailability and bioequivalence studies for immediate release solid oral dosage forms containing certain active moieties active ingredients based on a biopharmaceutic classification system february 1999 CDERFDA

Amidon GL Lennernas H Shah VP Crison JRA A theoretical basis for a biopharmaceutic drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharm Res 12 413-420 (1995)

Guidance for industry immediate release solid oral dosage forms scale up and post approval changes november 1995 CDERFDA

Medicamento generico from website httpwwwAnvisaGo

Devane J Oral drug delivery technology addressing the solubility permeability paradigm pharm Technol 68-74 november 1998

Amidon G LLennernaumls H Shah V P And crisonj R A theoretical basis for a biopharmaceutics drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharmaceutical research 12 413-420 (1995)

Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA CDER 1997 1048603httpwwwfdagovcderguidance1713bp1pdf

Guidance for Industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System FDA CDER August 2000 httpwwwfdagovcderguidance3618fnlhtm

Thank you

• BIOPHARMACEUTICS CLASSIFICATION SYSTEM
• Contents
• Introduction
• Slide 4
• Slide 5
• Biopharmaceutics Classification System
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• DISSOLUTION DETERMINATION
• CLASS BOUNDARIES
• BCS Class Boundaries Objectives
• Slide 15
• BCS -Implications for drug development
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Applications of BCS in oral drug delivery technology
• Class II - High Permeability Low Solubility
• Slide 27
• Slide 28
• Biowaiver
• Waiver of In Vivo Bioequivalence Study based on
• BCS BIOWAIVER
• REQUEST FOR BIOWAIVERS
• Limitations of BCS as a Predictor of Drug Disposition
• Conclusion
• References
• Slide 36
• Slide 37

References Draft guidance for industry waiver of in vivo

bioavailability and bioequivalence studies for immediate release solid oral dosage forms containing certain active moieties active ingredients based on a biopharmaceutic classification system february 1999 CDERFDA

Amidon GL Lennernas H Shah VP Crison JRA A theoretical basis for a biopharmaceutic drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharm Res 12 413-420 (1995)

Guidance for industry immediate release solid oral dosage forms scale up and post approval changes november 1995 CDERFDA

Medicamento generico from website httpwwwAnvisaGo

Devane J Oral drug delivery technology addressing the solubility permeability paradigm pharm Technol 68-74 november 1998

Amidon G LLennernaumls H Shah V P And crisonj R A theoretical basis for a biopharmaceutics drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharmaceutical research 12 413-420 (1995)

Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA CDER 1997 1048603httpwwwfdagovcderguidance1713bp1pdf

Guidance for Industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System FDA CDER August 2000 httpwwwfdagovcderguidance3618fnlhtm

Thank you

• BIOPHARMACEUTICS CLASSIFICATION SYSTEM
• Contents
• Introduction
• Slide 4
• Slide 5
• Biopharmaceutics Classification System
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• DISSOLUTION DETERMINATION
• CLASS BOUNDARIES
• BCS Class Boundaries Objectives
• Slide 15
• BCS -Implications for drug development
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Applications of BCS in oral drug delivery technology
• Class II - High Permeability Low Solubility
• Slide 27
• Slide 28
• Biowaiver
• Waiver of In Vivo Bioequivalence Study based on
• BCS BIOWAIVER
• REQUEST FOR BIOWAIVERS
• Limitations of BCS as a Predictor of Drug Disposition
• Conclusion
• References
• Slide 36
• Slide 37

Devane J Oral drug delivery technology addressing the solubility permeability paradigm pharm Technol 68-74 november 1998

Amidon G LLennernaumls H Shah V P And crisonj R A theoretical basis for a biopharmaceutics drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability Pharmaceutical research 12 413-420 (1995)

Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA CDER 1997 1048603httpwwwfdagovcderguidance1713bp1pdf

Guidance for Industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System FDA CDER August 2000 httpwwwfdagovcderguidance3618fnlhtm

Thank you

• BIOPHARMACEUTICS CLASSIFICATION SYSTEM
• Contents
• Introduction
• Slide 4
• Slide 5
• Biopharmaceutics Classification System
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• DISSOLUTION DETERMINATION
• CLASS BOUNDARIES
• BCS Class Boundaries Objectives
• Slide 15
• BCS -Implications for drug development
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Applications of BCS in oral drug delivery technology
• Class II - High Permeability Low Solubility
• Slide 27
• Slide 28
• Biowaiver
• Waiver of In Vivo Bioequivalence Study based on
• BCS BIOWAIVER
• REQUEST FOR BIOWAIVERS
• Limitations of BCS as a Predictor of Drug Disposition
• Conclusion
• References
• Slide 36
• Slide 37

Thank you

• BIOPHARMACEUTICS CLASSIFICATION SYSTEM
• Contents
• Introduction
• Slide 4
• Slide 5
• Biopharmaceutics Classification System
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• DISSOLUTION DETERMINATION
• CLASS BOUNDARIES
• BCS Class Boundaries Objectives
• Slide 15
• BCS -Implications for drug development
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Applications of BCS in oral drug delivery technology
• Class II - High Permeability Low Solubility
• Slide 27
• Slide 28
• Biowaiver
• Waiver of In Vivo Bioequivalence Study based on
• BCS BIOWAIVER
• REQUEST FOR BIOWAIVERS
• Limitations of BCS as a Predictor of Drug Disposition
• Conclusion
• References
• Slide 36
• Slide 37